5,004 results on '"Receptors, Fibroblast Growth Factor"'
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2. Study of Erdafitinib Intravesical Delivery System for Localized Bladder Cancer
- Published
- 2024
3. 慢性肾脏病循环中FGF23对心房纤维化的促进作用.
- Author
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高攀, 谢冰歆, 周赞东, and 刘彤
- Abstract
Objective To explore the possible mechanisms by which fibroblast growth factor (FGF) 23 promoted atrial fibrosis in circulation of chronic kidney disease (CKD) by binding to atrial tissue fibroblast growth factor receptor (FGFR) 4. Methods Twenty-two healthy male Sprague-Dawley (SD) rats were selected. Rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model (n=14). The remaining 8 rats were used as the sham group. The sham group (n=8) underwent the same surgery without removing renal tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography and pathological indices were monitored in both groups. Enzyme-linked immunosorbent assay (ELISA) method was used to determine the circulating levels of FGF23 in the two groups of rats. Transcriptomic analysis of left atrial tissue was performed to search for differentially expressed genes. Rat atrial fibroblasts were divided into the control group, the FGFR inhibitor group, the transforming growth factor- β (TGF-β) group and the TGF- β +FGFR inhibitor group. The expression levels of α -smooth muscle actin (α -SMA), collagen Ⅰ (Col Ⅰ) and phosphorylated protein kinase B (p-AKT) protein were detected by Western blot assay. Results Systolic blood pressure, blood urea nitrogen and creatinine were elevated in the CKD group of rats. Cardiac electrophysiological study showed that CKD could promote the occurrence of atrial fibrillation (AF) and atrioventricular block. Cardiac ultrasound suggested that the internal diameter of the left atrium was significantly increased in rats of the CKD group. Pathological findings showed that the left atrium in the CKD group underwent significant fibrosis, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. These changes were accompanied by higher circulating FGF23. Western blot results showed that FGFR4 expression was upregulated in the CKD group. After blocking the FGF23/FGFR4 signaling pathway in atrial fibroblasts, the fibrosis-related proteins α-SMA, Col Ⅰ and p-AKT/AKT were decreased. Conclusion CKD promotes the occurrence of AF by inducing both structural and electrical remodeling. Increased circulating FGF23 promotes atrial fibrosis by activating the downstream AKT pathway binding to FGFR4 in atrial tissue. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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4. A Study to Identify Participants With Urothelial Cancer and Fibroblast Growth Factor Receptor Gene Aberrations
- Published
- 2023
5. Personalisierte Therapie beim metastasierten Urothelkarzinom – Vision oder Wirklichkeit?
- Author
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Tahbaz, Rana and De Santis, Maria
- Published
- 2022
- Full Text
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6. Molekularpathologische Diagnostik des Harnblasenkarzinoms – prädiktive und prognostische Marker
- Author
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Rüschoff, Jan H. and Moch, Holger
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- 2022
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7. Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma.
- Author
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Hosni S, Kilian V, Klümper N, Gabbia D, Sieckmann K, Corvino D, Winkler A, Saponaro M, Wörsdörfer K, Schmidt D, Hahn O, Zanotto I, Bertlich M, Toma M, Bald T, Eckstein M, Hölzel M, Geyer M, Ritter M, Wachten D, De Martin S, and Alajati A
- Subjects
- Humans, Mice, Animals, Neuregulin-1, Receptors, Fibroblast Growth Factor, Signal Transduction, Protein Kinase Inhibitors pharmacology, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell pathology
- Abstract
Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies., Significance: Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment. See related commentary by Kolonin and Anastassiou, p. 648., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
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8. IRREVERSIBLE RETINAL PIGMENT EPITHELIUM TOXICITY ASSOCIATED WITH FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITOR THERAPY.
- Author
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Houghton OM
- Subjects
- Male, Humans, Aged, Retinal Pigment Epithelium, Receptors, Fibroblast Growth Factor, Tomography, Optical Coherence, Fluorescein Angiography, Retinal Diseases chemically induced, Macula Lutea
- Abstract
Purpose: Erdafitinib is a fibroblast growth factor receptor inhibitor indicated for the treatment of cancer. A case of fibroblast growth factor receptor inhibitor-associated retinopathy that resulted in significant visual symptoms and chronic subretinal abnormalities is reported., Methods: A 73-year-old man with a history of relapsed multiple myeloma was treated with erdafitinib. Soon after his fourth treatment cycle, he developed blurred vision in both eyes. Therapy with erdafitinib was subsequently discontinued., Results: Funduscopic examination and optical coherence tomography of both eyes revealed multifocal subretinal fluid in the macula of both eyes. Eleven weeks after cessation of the erdafitinib, the visual acuity improved but the patient reported bilateral annular scotomas. Evaluation was notable for resolution of the subretinal fluid with the development irregular subfoveal thickening in both eyes. The patient's symptoms improved, but the subfoveal abnormalities were persistent at 14 months follow-up., Conclusion: Erdafitinib may be associated with permanent retinal pigment epithelium toxicity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)
- Published
- 2024
- Full Text
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9. Identification of Piperazinyl-Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation.
- Author
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Ding W, Yan L, Sheng L, Chen S, Li Y, Cheng S, Luo L, Huang H, Shao H, and Zhang D
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- Humans, Mice, Animals, Receptors, Fibroblast Growth Factor, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 1, Signal Transduction, Cell Line, Cell Line, Tumor, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents pharmacology, Neoplasms drug therapy
- Abstract
The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the ( S )-3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H -indene scaffold containing a crucial 3-pyridyl group for the treatment of FGFR mutant cancers. The representative compound ( S )- 23 , which was identified through comprehensive evaluation, exhibited potent antiproliferative activity with GI
50 in the range of 6.4-10.4 nM against FGFR1 fusion protein-carrying, FGFR2-amplified, and FGFR2 mutant cancer cell lines and good antiproliferative activity against FGFR3 translocation and mutant FGFR4 cancer cell lines, as well as potency assessment against FGFR1-4 kinases. Moreover, compound ( S )- 23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound ( S )- 23 is a potential therapeutic agent for FGFR mutant tumors.- Published
- 2024
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10. Fibroblast Growth Factor Receptor Inhibitors Decrease Proliferation of Melanoma Cell Lines and Their Activity Is Modulated by Vitamin D.
- Author
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Piotrowska A, Nowak JI, Wierzbicka JM, Domżalski P, Górska-Arcisz M, Sądej R, Popiel D, Wieczorek M, and Żmijewski MA
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- Humans, Vitamin D metabolism, Receptors, Calcitriol metabolism, Cell Line, Tumor, Vitamins pharmacology, Receptors, Fibroblast Growth Factor, Cell Proliferation, Melanoma metabolism, Skin Neoplasms pathology
- Abstract
Regardless of the unprecedented progress in malignant melanoma treatment strategies and clinical outcomes of patients during the last twelve years, this skin cancer remains the most lethal one. We have previously documented that vitamin D and its low-calcaemic analogues enhance the anticancer activity of drugs including a classic chemotherapeutic-dacarbazine-and an antiangiogenic VEGFRs inhibitor-cediranib. In this study, we explored the response of A375 and RPMI7951 melanoma lines to CPL304110 (CPL110), a novel selective inhibitor of fibroblast growth factor receptors (FGFRs), and compared its efficacy with that of AZD4547, the first-generation FGFRs selective inhibitor. We also tested whether 1,25(OH)
2 D3 , the active form of vitamin D, modulates the response of the cells to these drugs. CPL304110 efficiently decreased the viability of melanoma cells in both A375 and RPMI7951 cell lines, with the IC50 value below 1 µM. However, the metastatic RPMI7951 melanoma cells were less sensitive to the tested drug than A375 cells, isolated from primary tumour site. Both tested FGFR inhibitors triggered G0/G1 cell cycle arrest in A375 melanoma cells and increased apoptotic/necrotic SubG1 fraction in RPMI7951 melanoma cells. 1,25(OH)2 D3 modulated the efficacy of CPL304110, by decreasing the IC50 value by more than 4-fold in A375 cell line, but not in RPMI7951 cells. Further analysis revealed that both inhibitors impact vitamin D signalling to some extent, and this effect is cell line-specific. On the other hand, 1,25(OH)2 D3 , have an impact on the expression of FGFR receptors and phosphorylation (FGFR-Tyr653/654). Interestingly, 1,25(OH)2 D3 and CPL304110 co-treatment resulted in activation of the ERK1/2 pathway in A375 cells. Our results strongly suggested possible crosstalk between vitamin D-activated pathways and activity of FGFR inhibitors, which should be considered in further clinical studies.- Published
- 2024
- Full Text
- View/download PDF
11. Treating Biliary Tract Cancers: New Targets and Therapies
- Author
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Joseph Ho, Constance Fiocco, and Kristen Spencer
- Subjects
Biliary Tract Neoplasms ,Adjuvants, Immunologic ,Humans ,Drug Therapy, Combination ,Pharmacology (medical) ,Immunotherapy ,Receptors, Fibroblast Growth Factor ,Neoadjuvant Therapy - Abstract
Biliary tract cancers (BTCs) are rare and aggressive tumors that typically present at an advanced stage when surgical resection is no longer considered a therapeutic option. While gemcitabine and cisplatin have been the mainstay of treatment, unique chemotherapy combination strategies, targeted therapies, and immunotherapies have had some clinical efficacy and remain promising areas for clinical research. The use of molecular profiling of BTCs has facilitated the development and subsequent clinical application of novel targeted therapy compounds. Among the many genomic alterations identified in BTCs, molecular abnormalities in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), human epidermal growth factor receptor 2 (HER2), and BRAF have been successfully targeted therapeutically in clinical trials. Furthermore, the expanded use of new chemotherapy combinations, targeted therapies, and immunotherapies into alternate clinical settings such as in the neoadjuvant and adjuvant spaces is an area of active investigation. The management of BTCs is rapidly evolving. In this article, we review the emerging targets and therapies in BTC.
- Published
- 2022
12. Phase 2 Study of Neoadjuvant FGFR Inhibition and Androgen Deprivation Therapy Prior to Prostatectomy
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Elizabeth Liow, Nicholas Howard, Chol-Hee Jung, Bernard Pope, Bethany K. Campbell, Anne Nguyen, Michael Kerger, Jonathan B. Ruddle, Angelyn Anton, Benjamin Thomas, Kevin Chu, Philip Dundee, Justin S. Peters, Anthony J. Costello, Andrew S. Ryan, Christopher M. Hovens, Ben Tran, and Niall M. Corcoran
- Subjects
Male ,Prostatectomy ,Neoplasm, Residual ,Urology ,Prostatic Neoplasms ,Androgen Antagonists ,Prostate-Specific Antigen ,Receptors, Fibroblast Growth Factor ,Neoadjuvant Therapy ,Fibroblast Growth Factors ,Oncology ,Androgens ,Humans ,RNA ,Neoplasm Recurrence, Local - Abstract
Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting.We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing.Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation.Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.
- Published
- 2022
13. AZD4547 and the Alleviation of Hepatoma Cell Sorafenib Resistance via the Promotion of Autophagy
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Shuixiang He, Hongxia Li, Yun Feng, Dan Zhang, Gaixia He, Yaping Liu, Yan Zhao, Xiaoyang Ren, Huanhuan Sun, Guifang Lu, Zhiyong Zhang, Li Ren, and Yan Yin
- Subjects
Pharmacology ,Cancer Research ,Carcinoma, Hepatocellular ,Liver Neoplasms ,Sorafenib ,Receptors, Fibroblast Growth Factor ,Piperazines ,digestive system diseases ,Cell Line ,Toll-Like Receptor 4 ,Cell Line, Tumor ,Benzamides ,Autophagy ,Humans ,Pyrazoles ,Molecular Medicine ,Beclin-1 ,Saline Solution ,Cell Proliferation - Abstract
Background: This study is part of a larger research effort to explore the molecular mechanism of hepatocellular carcinoma, reduce drug resistance and seek new targets. Objective: The objective of this study is to investigate the effect and mechanism of fibroblast growth factor receptor inhibitor AZD4547 on Sorafenib-resistant hepatoma cells. Methods: First, we constructed a Sorafenib-resistant hepatoma cell line Huh7R. Different groups of Huh7R cells were treated with Sorafenib, AZD4547, Sorafenib combined with AZD4547, and normal saline. The cell viability was detected by Cell Counting Kit-8. Then Fibroblast growth factor receptor and Toll-like receptor 4 were detected by Western blot, as well as the LC3 II/I, Beclin1, and P62. In addition, we used the autophagy inhibitor 3-methyladenine to identify the mechanism of AZD4547 combined with Sorafenib for inducing Sorafenib-resistant hepatoma cell death. Results: We find that AZD4547 combined with Sorafenib significantly inhibited the viability of Sorafenib-resistant hepatoma cell Huh7R. As for its mechanism, AZD4547 was able to inhibit fibroblast growth factor receptor activity, promote autophagy and regulate immunity. AZD4547 increased LC3 II/I, Beclin1, and Toll-like receptor 4 proteins, and decreased P62 protein level in Huh7R cells significantly when given in combination with sorafenib. Furthermore, 3-methyladenine inhibited autophagy and reversed the killing effect of the combination of AZD4547 and Sorafenib on Huh7R cells. Conclusion: The inhibition of fibroblast growth factor receptor activity by AZD4547 can significantly enhance autophagy and immune response, as well as promote the death of Sorafenib-resistant hepatoma cells.
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- 2022
14. Novel parameter for cancer chemosensitivity to fibroblast growth factor receptor inhibitors
- Author
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Shoichi Kitano, Takehito Yamamoto, and Makoto Mark Taketo
- Subjects
ErbB Receptors ,Cancer Research ,Oncology ,Neoplasms ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,General Medicine ,Receptor, Fibroblast Growth Factor, Type 2 ,Protein Kinase Inhibitors ,Receptors, Fibroblast Growth Factor ,Signal Transduction - Abstract
Fibroblast growth factor receptor inhibitors (FGFRi) were introduced into clinical trials on several cancer types and found to be particularly efficacious on urothelial cancer and cholangiocarcinoma. Although many enrolled patients responded well in clinical trials, there were some patients who did not respond to FGFRi even though their tumors carried the genomic changes that met the enrollment criteria. As already established, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) share the downstream signaling pathway of MAPK activation. Accordingly, it is conceivable that targeted inhibition of FGFR alone could leave the MAPK signaling unaffected when the signaling through EGFR is relatively strong. To test this hypothesis, we calculated here the FGFR to EGFR mRNA ratio (F/E for short) of biliary tract and urothelial cancer cell lines utilized in preclinical studies. In six biliary tract cancer cell lines, two responsive lines had an F/E of 9.5 and 9.0, whereas the F/E of four nonresponsive lines was 0.1-1.8. In 22 urothelial cancer cell lines, four of the five responsive lines showed an F/E of 2.8-4.9 (median, 3.6), whereas the F/E range of 17 nonresponsive lines was 0.01-2.7 (median, 0.6) (p = 0.004). We further investigated our 47 patient-derived colorectal cancer-stem cell spheroid lines. The 18 responsive lines showed relatively high F/E (median, 16.4), whereas 29 nonresponsive lines had low F/E (median, 9.2) (p = 0.0006). These results suggest that F/E is another strong predictor of responses to FGFRi that is as useful as the current genomic criteria based solely on the FGFR genomic changes.
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- 2022
15. The path to personalized treatment in advanced and metastatic biliary tract cancers: a review of new targeted therapies and immunotherapy
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Anne, Demols, Ana-Maria, Bucalau, and Laura, Mans
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Cancer Research ,Biliary Tract Neoplasms ,Oncology ,Humans ,Immunotherapy ,Molecular Targeted Therapy ,Cisplatin ,Precision Medicine ,Receptors, Fibroblast Growth Factor - Abstract
To summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials.For the first time since gemcitabine-cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine-cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600E mutations or KRASG12C mutations.In this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.
- Published
- 2022
16. The fibroblast growth factor receptor antagonist SSR128129E inhibits fat accumulation via suppressing adipogenesis in mice
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Xinzhi Zhang, Xin Wen, Geng Hu, Qiang Zhang, Qianying Sun, Yanxin Jia, Yan Liu, Hai Lin, and Haifang Li
- Subjects
Male ,Adipogenesis ,Indolizines ,Thermogenesis ,General Medicine ,Diet, High-Fat ,Receptors, Fibroblast Growth Factor ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,Mice ,Adipose Tissue, Brown ,Genetics ,Animals ,Humans ,ortho-Aminobenzoates ,Obesity ,Molecular Biology - Abstract
AS an allosteric inhibitor of fibroblast growth factor receptors (FGFRs), SSR128129E (SSR) extensively inhibits the fibroblast growth factor (FGF) signaling. Given the metabolic importance of FGFs and the global epidemic of obesity, we explored the effect of SSR on fat metabolism.Three-week-old male mice were administered intragastrically with SSR (30 mg/kg/day) or PBS for 5 weeks. The effects of SSR on white and brown fat metabolism were investigated by respiratory metabolic monitoring, histological assessment and molecular analysis. Results indicated that SSR administration significantly reduced the body weight gain and the fat content of mice. SSR did not increase, but decreased the thermogenic capability of both brown and white fat. However, SSR markedly suppressed adipogenesis of adipose tissues. Further study demonstrated the involvement of ERK signaling in the action of SSR.SSR may be a promising drug candidate for the prevention of obesity via suppressing adipogenesis. However, the influence of SSR on thermogenesis in humans should be further investigated before its clinical application.
- Published
- 2022
17. The novel FGFR inhibitor F1-7 induces DNA damage and cell death in colon cells
- Author
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Yanan Liu, Liting Zhang, Xiaolu Chen, Daoxing Chen, Xueqin Shi, Jiali Song, Jianzhang Wu, Fengyu Huang, Qinqin Xia, Youqun Xiang, Xiaohui Zheng, and Yuepiao Cai
- Subjects
Mice ,Cancer Research ,Cell Death ,Oncology ,Cell Line, Tumor ,Colonic Neoplasms ,Animals ,Humans ,Protein Kinase Inhibitors ,Receptors, Fibroblast Growth Factor ,Article ,Cell Proliferation ,DNA Damage - Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.
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- 2022
18. RAB11A Expression Is Associated With Cancer Aggressiveness Through Regulation of FGFR-Signaling in Lung Squamous Cell Carcinoma
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Navchaa, Gombodorj, Yoko, Azuma, Takehiko, Yokobori, Bilguun, Erkhem-Ochir, Takayuki, Kosaka, Yoichi, Ohtaki, Seshiru, Nakazawa, Akira, Mogi, Toshiki, Yajima, Hiroyuki, Kuwano, Hiroshi, Saeki, and Ken, Shirabe
- Subjects
Lung Neoplasms ,Receptors, Fibroblast Growth Factor ,Gene Expression Regulation, Neoplastic ,Oncology ,rab GTP-Binding Proteins ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Carcinoma, Squamous Cell ,Humans ,Surgery ,Laryngeal Neoplasms ,Lung ,Cell Proliferation ,Monomeric GTP-Binding Proteins - Abstract
Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling.Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo.The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells.As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.
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- 2022
19. Ipatasertib (GDC-0068) and erdafitinib co-treatment for inducing mitochondrial apoptosis through Bim upregulation in bladder cancer cells
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Changhua, Hu, Xiaosong, Shang, Tongning, Zheng, Xiaoquan, Hu, and Yu, Zhao
- Subjects
Bcl-2-Like Protein 11 ,Biophysics ,Apoptosis ,Cell Biology ,Receptors, Fibroblast Growth Factor ,Biochemistry ,Piperazines ,Mitochondria ,Up-Regulation ,Pyrimidines ,Urinary Bladder Neoplasms ,Quinoxalines ,Humans ,Pyrazoles ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Molecular Biology - Abstract
Bladder cancer (BC) is a common malignancy of the urological system that still lacks effective treatment. It is frequently characterised by dysregulation of fibroblast growth factor receptor (FGFR) signalling. FGFR inhibitors have been proven as a promising treatment for BC in clinical settings. Besides the FGFR signalling, the therapeutic effects of FGFR inhibitors are often limited owing to various mechanisms, such as the activation of the Akt signalling pathway. Therefore, this study aimed to examine the synergistic effects of ipatasertib, a FGFR inhibitor, and erdafitinib, an Akt inhibitor, in BC cells. Ipatasertib and erdafitinib co-treatment synergistically inhibited cell proliferation and induced BC cell death. Mechanically, ipatasertib and erdafitinib induced the activation of Bax, an essential protein for cell death. Moreover, erdafitinib, which inhibited the Akt signalling pathway, is responsible for Bim upregulation, a condition critical to achieving the synergistic effects. Therefore, our data suggest that ipatasertib and erdafitinib co-treatment is a promising strategy for BC.
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- 2022
20. Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell‐like properties and phosphoinositide 3‐kinase inhibitor insensitivity
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Khoa A. Nguyen, Madison J. Keith, Stephen B. Keysar, Spencer C. Hall, Anamol Bimali, Antonio Jimeno, Xiao‐Jing Wang, and Christian D. Young
- Subjects
Keratinocytes ,Cancer Research ,Squamous Cell Carcinoma of Head and Neck ,Receptors, Fibroblast Growth Factor ,Article ,ErbB Receptors ,Phosphatidylinositol 3-Kinases ,Head and Neck Neoplasms ,Cell Line, Tumor ,Carcinoma, Squamous Cell ,Neoplastic Stem Cells ,Tumor Microenvironment ,Humans ,Phosphatidylinositol 3-Kinase ,Precancerous Conditions ,Molecular Biology ,Phosphoinositide-3 Kinase Inhibitors - Abstract
Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a "precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.
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- 2022
21. Resistance mechanism to fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma.
- Author
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Lamarca A, Ostios L, McNamara MG, Garzon C, Gleeson JP, Edeline J, Herrero A, Hubner RA, Moreno V, and Valle JW
- Subjects
- Humans, Receptors, Fibroblast Growth Factor, Receptor, Fibroblast Growth Factor, Type 2 genetics, Protein Kinase Inhibitors adverse effects, Disease Progression, Bile Ducts, Intrahepatic metabolism, Bile Ducts, Intrahepatic pathology, Cholangiocarcinoma drug therapy, Cholangiocarcinoma metabolism, Bile Duct Neoplasms drug therapy, Bile Duct Neoplasms pathology
- Abstract
Precision medicine is a major achievement that has impacted on management of patients diagnosed with advanced cholangiocarcinoma (CCA) over the last decade. Molecular profiling of CCA has identified targetable alterations, such as fibroblast growth factor receptor-2 (FGFR-2) fusions, and has thus led to the development of a wide spectrum of compounds. Despite favourable response rates, especially with the latest generation FGFRi, there are still a proportion of patients who will not achieve a radiological response to treatment, or who will have disease progression as the best response. In addition, for patients who do respond to treatment, secondary resistance frequently develops and mechanisms of such resistance are not fully understood. This review will summarise the current state of development of FGFR inhibitors in CCA, their mechanism of action, activity, and the hypothesised mechanisms of resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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22. Futibatinib: second EMA approval for FGFR inhibitor in cholangiocarcinoma.
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Lamarca A and Vogel A
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- Humans, Receptors, Fibroblast Growth Factor, Bile Ducts, Intrahepatic pathology, Cholangiocarcinoma drug therapy, Cholangiocarcinoma pathology, Bile Duct Neoplasms drug therapy, Bile Duct Neoplasms pathology
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- 2023
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23. Investigating cellular dynamics in tunicates.
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Cota CD
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- Animals, Receptor Protein-Tyrosine Kinases, Receptors, Fibroblast Growth Factor, Urochordata genetics
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- 2023
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24. Exploiting the fibroblast growth factor receptor-1 vulnerability to therapeutically restrict the MYC-EZH2-CDKN1C axis-driven proliferation in Mantle cell lymphoma.
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Sircar A, Singh S, Xu-Monette ZY, Coyle KM, Hilton LK, Chavdoula E, Ranganathan P, Jain N, Hanel W, Tsichlis P, Alinari L, Peterson BR, Tao J, Muthusamy N, Baiocchi R, Epperla N, Young KH, Morin R, and Sehgal L
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- Adult, Humans, Cell Death, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p57 metabolism, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Receptors, Fibroblast Growth Factor, Signal Transduction, Tumor Microenvironment genetics, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell metabolism
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Mantle cell lymphoma (MCL) is a lethal hematological malignancy with a median survival of 4 years. Its lethality is mainly attributed to a limited understanding of clinical tumor progression and resistance to current therapeutic regimes. Intrinsic, prolonged drug treatment and tumor-microenvironment (TME) facilitated factors impart pro-tumorigenic and drug-insensitivity properties to MCL cells. Hence, elucidating neoteric pharmacotherapeutic molecular targets involved in MCL progression utilizing a global "unified" analysis for improved disease prevention is an earnest need. Using integrated transcriptomic analyses in MCL patients, we identified a Fibroblast Growth Factor Receptor-1 (FGFR1), and analyses of MCL patient samples showed that high FGFR1 expression was associated with shorter overall survival in MCL patient cohorts. Functional studies using pharmacological intervention and loss of function identify a novel MYC-EZH2-CDKN1C axis-driven proliferation in MCL. Further, pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell-cycle arrest and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. We performed extensive pre-clinical assessments in multiple in-vivo model systems to confirm the therapeutic potential of erdafitinib in MCL and demonstrated FGFR1 as a viable therapeutic target in MCL., (© 2023. The Author(s).)
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- 2023
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25. First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid Tumors
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James J. Harding, Christiane Jungels, Jean-Pascal Machiels, David C. Smith, Chris Walker, Tao Ji, Ping Jiang, Xin Li, Ekaterine Asatiani, Eric Van Cutsem, Ghassan K. Abou-Alfa, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, and UCL - (SLuc) Service d'oncologie médicale
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Diarrhea ,EXPRESSION ,Cancer Research ,BILE-ACID SYNTHESIS ,Science & Technology ,Maximum Tolerated Dose ,IDENTIFICATION ,CASCADE ,POTENT ,Liver Neoplasms ,HEPATOCELLULAR CARCINOMAS ,Receptors, Fibroblast Growth Factor ,SIGNAL ,Bile Acids and Salts ,Oncology ,FXR ,Neoplasms ,FGFR4 ,Humans ,Pharmacology (medical) ,Female ,Receptor, Fibroblast Growth Factor, Type 4 ,Protein Kinase Inhibitors ,Life Sciences & Biomedicine ,SUPPRESSION - Abstract
INTRODUCTION: Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. METHODS: This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. RESULTS: Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations
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- 2023
26. In vitro and in vivo assessment of the effect of biodegradable magnesium alloys on osteogenesis
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Ding Li, Dechuang Zhang, Qi Yuan, Lihong Liu, Hui Li, Liang Xiong, Xiaoning Guo, Yang Yan, Kun Yu, Yilong Dai, Tao Xiao, Yuncang Li, and Cuie Wen
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Biomaterials ,Osteogenesis ,Alloys ,Biomedical Engineering ,Animals ,Magnesium ,General Medicine ,Receptors, Fibroblast Growth Factor ,Molecular Biology ,Biochemistry ,Rats ,Biotechnology - Abstract
Magnesium (Mg) and some of its alloys are considered promising biodegradable metallic biomaterials for bone implant applications. The osteogenesis effect of Mg alloys is widely reported; however, the underlying mechanisms are still not clear. In this study, pure Mg, Mg-3Zn, and Mg-2Zn-1Mn were prepared, and their degradation behavior, biocompatibility, and osteogenesis effect were systematically assessed both in vitro and in vivo. Primary rat bone marrow-derived mesenchymal stem cells (BMSCs) were used to evaluate the biocompatibility of the prepared Mg alloys, and a rat femur fracture model was used to assess the stimulating effect of these alloys on bone-tissue formation. Mg-2Zn-1Mn showed higher corrosion resistance and more stable degradation behavior than pure Mg and Mg-3Zn. Extracts of the three materials showed significant stimulating effects on osteogenic differentiation of BMSCs along with non-cytotoxicity. Implantation of Mg-2Zn-1Mn wires into the femur of rats demonstrated superior histocompatibility, stable degradation, and notable promotion of osteogenesis without systemic toxicity. Moreover, the results of both in vitro and in vivo assessments demonstrated that bone morphogenetic proteins and fibroblast growth factor receptors are involved in the stimulating effect of Mg alloys. STATEMENT OF SIGNIFICANCE: This work reports the degradation behavior, biocompatibility, and osteogenic effect of pure Mg and Mg-3Zn and Mg-2Zn-1Mn alloys in both in vitro and in vivo conditions. Mg-2Zn-1Mn showed higher corrosion resistance and more stable degradation behavior than pure Mg and Mg-3Zn. The extracts of the three materials showed a significant stimulating effect on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) along with non-cytotoxicity. Mg-2Zn-1Mn wires implanted into the femur of rats showed good histocompatibility, stable degradation, and notable promotion of osteogenesis without systemic toxicity. The results of the present study suggest that bone morphogenetic proteins (BMPs) and fibroblast growth factor receptors (FGFRs) are involved in the stimulating effect of Mg alloys on osteogenesis.
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- 2022
27. The role of fibroblast growth factor 8 in cartilage development and disease
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Haoran Chen, Yujia Cui, Demao Zhang, Jing Xie, and Xuedong Zhou
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Fibroblast Growth Factors ,Cartilage ,Chondrocytes ,Fibroblast Growth Factor 8 ,Molecular Medicine ,Receptor, Fibroblast Growth Factor, Type 1 ,Cell Biology ,Chondrogenesis ,Receptors, Fibroblast Growth Factor ,Cells, Cultured - Abstract
Fibroblast growth factor 8 (FGF-8), also known as androgen-induced growth factor (AIGF), is presumed to be a potent mitogenic cytokine that plays important roles in early embryonic development, brain formation and limb development. In the bone environment, FGF-8 produced or received by chondrocyte precursor cells binds to fibroblast growth factor receptor (FGFR), causing different levels of activation of downstream signalling pathways, such as phospholipase C gamma (PLCγ)/Ca
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- 2022
28. FGF signalling facilitates cervical cancer progression
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Hiba‐Tun‐Noor Afshan Mahmood, Elena Tomas Bort, Anthony J. Walker, Richard P. Grose, and Athina‐Myrto Chioni
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Fibroblast Growth Factors ,Papillomavirus Infections ,cancer ,Humans ,Uterine Cervical Neoplasms ,Female ,Cell Biology ,Receptor, Fibroblast Growth Factor, Type 2 ,Protein Processing, Post-Translational ,Receptors, Fibroblast Growth Factor ,Molecular Biology ,Biochemistry ,Signal Transduction - Abstract
Cervical cancer is one of the most frequently diagnosed cancers in women worldwide. While cervical cancer is caused by human papillomavirus (HPV), not all females infected with HPV develop the disease, suggesting that other factors might facilitate its progression. Growing evidence supports the involvement of the fibroblast growth factor receptor (FGFR) axis in several cancers, including gynecological. However, for cervical cancer, the molecular mechanisms that underpin the disease remain poorly understood, including the role of FGFR signaling. The aim of this study was to investigate FGF(R) signaling in cervical cancer through bioinformatic analysis of cell line and patient data and through detailed expression profiling, manipulation of the FGFR axis, and downstream phenotypic analysis in cell lines (HeLa, SiHa, and CaSki). Expression (protein and mRNA) analysis demonstrated that FGFR1b/c, FGFR2b/c, FGFR4, FGF2, FGF4, and FGF7 were expressed in all three lines. Interestingly, FGFR1 and 2 localized to the nucleus, supporting that nuclear FGFRs could act as transcription factors. Importantly, 2D and 3D cell cultures demonstrated that FGFR activation can facilitate cell functions correlated with invasive disease. Collectively, this study supports an association between FGFR signaling and cervical cancer progression, laying the foundations for the development of therapeutic approaches targeting FGFR in this disease.
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- 2022
29. Exposure–response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma
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Anne-Gaëlle Dosne, Elodie Valade, Nele Goeyvaerts, Peter De Porre, Anjali Avadhani, Anne O’Hagan, Lilian Y. Li, Daniele Ouellet, and Juan Jose Perez Ruixo
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Male ,Pharmacology ,Carcinoma, Transitional Cell ,Cancer Research ,Dose-Response Relationship, Drug ,Middle Aged ,Toxicology ,Receptors, Fibroblast Growth Factor ,Progression-Free Survival ,Survival Rate ,Urinary Bladder Neoplasms ,Oncology ,Quinoxalines ,Humans ,Pyrazoles ,Female ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Aged - Abstract
Background Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. Results Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46–0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67–0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02–1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. Conclusions The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio. Clinical trial registration number NCT02365597.
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- 2022
30. Intrahepatic cholangiocyte regeneration from an Fgf‐dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome
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Keith P. Gates, P. Duc Si Dong, Jonathan Matalonga, Jiaye He, Chong Chen, Lindsey Barske, Jan Huisken, Dan Cao, Yi Yang, Chengjian Zhao, Alyssa Graves, Xiangyu Pan, and Joseph J. Lancman
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Notch signaling pathway ,Biology ,Fibroblast growth factor ,Article ,Cholangiocyte ,Bile Ducts, Extrahepatic ,Alagille syndrome ,medicine ,Animals ,Humans ,cardiovascular diseases ,Progenitor cell ,Zebrafish ,Receptors, Notch ,Hepatology ,Regeneration (biology) ,Calcium-Binding Proteins ,Mesenchymal stem cell ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,Receptors, Fibroblast Growth Factor ,Liver Regeneration ,Cell biology ,Alagille Syndrome ,Disease Models, Animal ,Bile Ducts, Intrahepatic ,Liver ,Cell Transdifferentiation ,Jagged-1 Protein ,Signal Transduction - Abstract
Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene JAGGED1, leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown.Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch-dependent mechanism. Combining multiple lineage tracing strategies with whole-liver three-dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte-to-IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue-specific mosaic analysis with an inducible dominant-negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids.Our data show that IHD cells regenerate upon resumption of Jagged/Notch signaling, from multipotent progenitors originating from an Fgf-dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced.
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- 2021
31. Case Report: Erdafitinib-induced Central Serous Chorioretinopathy
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Richard T, Claiborne and Grace L, Tsan
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Aged, 80 and over ,Male ,Carcinoma, Transitional Cell ,Receptors, Fibroblast Growth Factor ,United States ,Ophthalmology ,Central Serous Chorioretinopathy ,Urinary Bladder Neoplasms ,Quinoxalines ,Quality of Life ,Humans ,Pyrazoles ,Female ,Protein Kinase Inhibitors ,Optometry - Abstract
Erdafitinib is the first fibroblast growth factor receptor inhibitor approved by the U.S. Food and Drug Administration in April 2019 for the treatment of locally advanced and unresectable or metastatic urothelial carcinoma. Central serous chorioretinopathy is a common ocular adverse effect requiring frequent monitoring with ophthalmic examination.This study aimed to increase awareness of erdafitinib-induced central serous chorioretinopathy, highlight erdafitinib dose management guidelines, and emphasize the importance of collaborating with oncologists to prevent adverse visual consequences.An 80-year-old patient with an advanced urothelial cancer with fibroblast growth factor receptor mutations developed central serous chorioretinopathy when he was treated with daily 8 mg of erdafitinib. The erdafitinib-induced central serous chorioretinopathy resolved completely after the discontinuation of erdafitinib. He was then treated with daily 6 mg of erdafitinib and again developed central serous chorioretinopathy, which resolved completely upon discontinuation of the medication. The patient then decided to stop treatment with erdafitinib.Erdafitinib, a potent tyrosine kinase receptor inhibitor of fibroblast growth factor receptors 1 to 4, demonstrates antitumor activity in advanced urothelial carcinoma with fibroblast growth factor receptor mutations with a response rate of approximately 40%. However, central serous chorioretinopathy develops in 25% of patients treated with a daily 8-mg dose of erdafitinib. Although most mild to moderate erdafitinib-induced central serous chorioretinopathies resolve with dose interruption or reduction, occasionally discontinuation of the medication is necessary. Therefore, careful coordination with oncologists is important to assess the impact of erdafitinib on vision, quality of life, and survival prognosis.
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- 2021
32. AZD4547 targets the FGFR/Akt/SOX2 axis to overcome paclitaxel resistance in head and neck cancer
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Michael Ittmann, Neslisah Barlak, Betul Gundogdu, Omer Faruk Karatas, Abdulmelik Aytatli, Hasan Onur Caglar, Arzu Tatar, and Fatma Sanli
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Cancer Research ,Paclitaxel ,Fibroblast growth factor ,Piperazines ,Phosphatidylinositol 3-Kinases ,stomatognathic system ,SOX2 ,Cell Line, Tumor ,medicine ,Humans ,Receptor ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Glycogen Synthase Kinase 3 beta ,Chemistry ,SOXB1 Transcription Factors ,General Medicine ,medicine.disease ,Receptors, Fibroblast Growth Factor ,Head and neck squamous-cell carcinoma ,stomatognathic diseases ,Oncology ,Drug Resistance, Neoplasm ,Head and Neck Neoplasms ,Fibroblast growth factor receptor ,Benzamides ,embryonic structures ,Cancer research ,Pyrazoles ,Molecular Medicine ,biological phenomena, cell phenomena, and immunity ,Stem cell ,Proto-Oncogene Proteins c-akt - Abstract
Development of chemoresistance is one of the major obstacles to the treatment of head and neck squamous cell carcinoma (HNSCC). The PI3K/Akt pathway, involved in drug resistance, has been found to be overactivated in > 90% of HNSCCs. Aberrant activation of the FGF receptors (FGFRs) has been reported to cause overactivation of the PI3K/Akt pathway and to be associated with the maintenance of stem cell features, which is controlled via SOX2 expression. In this study, we aimed at investigating the potential of using AZD4547, an orally bioavailable FGFR inhibitor, to overcome taxol-resistance by targeting the FGFR/Akt/SOX2 axis in HNSCC. We initially evaluated FGFR2 and SOX2 expression using in silico tools. We analyzed the FGFR/Akt/SOX2 axis in normal/tumor tissue pairs and in recombinant FGF2 treated HNSCC cells. Next, we explored the effects of AZD4547 alone and in combination with taxol on the proliferation, migration and colony forming capacities of parental/taxol-resistant cells using in vitro models. We found that the p-FGFR, p-AKT, p-GSK-3β and SOX2 expression levels were higher in tumor tissues than in its corresponding normal tissues, and that AZD4547 effectively suppressed the expression of FGFR and its downstream targets in recombinant FGF2 treated HNSCC cells. We also found that AZD4547 diminished the viability, migration and colony forming capacity of HNSCC cells, and that co-treatment with taxol potentiated the impact of taxol on these cells. Finally, we found that AZD4547 inhibited the overexpressed FGFR/Akt/SOX2 axis and profoundly suppressed cancer-related phenotypes in taxol-resistant HNSCC cells. From our data we conclude that AZD4547 may increase the impact of taxol during HNSCC treatment. We suggest AZD4547 as a therapeutic agent to overcome taxol-resistance.
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- 2021
33. FGFR-inhibitor-mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces adaptive therapeutic resistance
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Xiaoqing Wang, Raga Vadhi, Pei-Lun Kao, Alok K. Tewari, Kin-Hoe Chow, Renee C. Geck, Aliya Jaber, X. Shirley Liu, Alba Font-Tello, Tengfei Xiao, Paloma Cejas, Klothilda Lim, Hui Liu, Xintao Qiu, Murry Morrow, Henry W. Long, Yingtian Xie, Smitha Yerrum, Yihao Li, Quang-Dé Nguyen, Alex Toker, Myles Brown, and Kristen L Jones
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Chromosomal Proteins, Non-Histone ,FGFR Inhibition ,Antineoplastic Agents ,Triple Negative Breast Neoplasms ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Epigenesis, Genetic ,Downregulation and upregulation ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Molecular Targeted Therapy ,Epigenetics ,Amino Acids ,Chemistry ,Phenylurea Compounds ,DNA Helicases ,Nuclear Proteins ,Drug Synergism ,YAP-Signaling Proteins ,Cell Biology ,Chromatin Assembly and Disassembly ,Receptors, Fibroblast Growth Factor ,Xenograft Model Antitumor Assays ,SWI/SNF ,Cell biology ,Chromatin ,Gene Expression Regulation, Neoplastic ,Pyrimidines ,Drug Resistance, Neoplasm ,Fibroblast growth factor receptor ,Multiprotein Complexes ,Cancer cell ,Female ,biological phenomena, cell phenomena, and immunity ,Signal Transduction ,Transcription Factors - Abstract
How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodelling, leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters, resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenograft models. Collectively, these findings reveal a feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provides potential therapeutic strategies to overcome this mechanism of resistance. Li et al. define an adaptive resistance mechanism against FGFR inhibitor treatment in breast cancer attributed to loss of BRG1 chromatin recruitment, reactivation of YAP-dependent enhancers and upregulation of amino acid-induced mTORC1 activity.
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- 2021
34. Resound Trial: A phase 2 study of regorafenib in patients with thymoma (type B2‐B3) and thymic carcinoma previously treated with chemotherapy
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Silvia Bozzarelli, Federica D'Antonio, Nunzio Digiacomo, Armando Santoro, Federica Borea, Paolo Andrea Zucali, Fabio Conforti, Nadia Cordua, Matteo Perrino, Tommaso De Pas, Fabio De Vincenzo, and Laura Giordano
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Cancer Research ,medicine.medical_specialty ,Thymoma ,Pyridines ,medicine.medical_treatment ,Phases of clinical research ,Gastroenterology ,Disease-Free Survival ,Receptor, Platelet-Derived Growth Factor beta ,chemistry.chemical_compound ,Regorafenib ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Thymic carcinoma ,Chemotherapy ,business.industry ,Phenylurea Compounds ,Thymus Neoplasms ,medicine.disease ,Receptors, Fibroblast Growth Factor ,Vascular endothelial growth factor ,Receptors, Vascular Endothelial Growth Factor ,Oncology ,chemistry ,Neoplasm Recurrence, Local ,business ,Progressive disease - Abstract
Background Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor β (PDGFR-β), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2-B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum-containing chemotherapy. Methods A Fleming single-arm, single-stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8-week progression-free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥50% (≥8 of 19 evaluable patients progression-free at 2 months). Results From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi-criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8-week PFS rate was 78.9% (15 of 19 patients). Grade 3-4 treatment-related adverse events were observed in 10 patients (52.6%). Conclusions The primary end point of this study was reached. The high rate of PR (Choi-criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.
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- 2021
35. Tyrosine kinases regulate chondrocyte hypertrophy
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L. Legeai-Mallet, H. Domenech Garcia, G.J.V.M. van Osch, and M.N. Ferrao Blanco
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Biomedical Engineering ,Chondrocyte hypertrophy ,Osteoarthritis ,Proto-Oncogene Proteins c-fyn ,Receptor Tyrosine Kinase-like Orphan Receptors ,Muscle hypertrophy ,Receptor, IGF Type 1 ,Chondrocytes ,Rheumatology ,Medicine ,Humans ,Orthopedics and Sports Medicine ,Receptor, trkA ,Discoidin Domain Receptors ,Protein Kinase Inhibitors ,Janus kinase inhibitor ,Tofacitinib ,business.industry ,Hypertrophy ,Janus Kinase 2 ,Protein-Tyrosine Kinases ,medicine.disease ,Receptors, Fibroblast Growth Factor ,ErbB Receptors ,Rheumatoid arthritis ,Focal Adhesion Protein-Tyrosine Kinases ,Cancer research ,Signal transduction ,business ,Tyrosine kinase ,Signal Transduction - Abstract
Osteoarthritis (OA) is a major health problem worldwide that affects the joints and causes severe disability. It is characterized by pain and low-grade inflammation. However, the exact pathogenesis remains unknown and the therapeutic options are limited. In OA articular chondrocytes undergo a phenotypic transition becoming hypertrophic, which leads to cartilage damage, aggravating the disease. Therefore, a therapeutic agent inhibiting hypertrophy would be a promising disease-modifying drug. The therapeutic use of tyrosine kinase inhibitors has been mainly focused on oncology, but the Food and Drug Administration (FDA) approval of the Janus kinase inhibitor Tofacitinib in Rheumatoid Arthritis has broadened the applicability of these compounds to other diseases. Interestingly, tyrosine kinases have been associated with chondrocyte hypertrophy. In this review, we discuss the experimental evidence that implicates specific tyrosine kinases in signaling pathways promoting chondrocyte hypertrophy, highlighting their potential as therapeutic targets for OA.
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- 2021
36. Discovery of 2-Amino-7-sulfonyl-7
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Wuchen, Xie, Siyu, Yang, Li, Liang, Meng, Wang, Wen, Zuo, Yan, Lei, Yanmin, Zhang, Weifang, Tang, Tao, Lu, Yadong, Chen, and Yulei, Jiang
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Mice ,Carcinoma, Hepatocellular ,Pyrimidines ,Cell Line, Tumor ,Liver Neoplasms ,Mutation ,Humans ,Animals ,Antineoplastic Agents ,Receptors, Fibroblast Growth Factor ,Protein Kinase Inhibitors ,Cell Proliferation - Abstract
Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7
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- 2022
37. Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma
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Wengang Zhang, Handai Xia, Rui Yang, Yuqing Zhang, Qi Zheng, Xiaoling Shang, Ni Liu, Xinchun Ma, Chenxi Wei, Hang Chen, Xin Mu, Xiuwen Wang, and Yanguo Liu
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Antineoplastic Agents, Immunological ,Skin Neoplasms ,Mutation ,Immunology ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Immunology and Allergy ,Immune Checkpoint Inhibitors ,Melanoma ,Receptors, Fibroblast Growth Factor - Abstract
BackgroundThe emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma.MethodsThe Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort.ResultsIn the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts.ConclusionsOur study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.
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- 2022
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38. Fibroblast growth factor 10 attenuates chronic obstructive pulmonary disease by protecting against glycocalyx impairment and endothelial apoptosis
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Tian Jiang, Weiping Hu, Shaoyuan Zhang, Changhao Ren, Siyun Lin, Zhenyu Zhou, Hao Wu, Jun Yin, and Lijie Tan
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Emphysema ,Mice ,Pulmonary Disease, Chronic Obstructive ,Pulmonary Emphysema ,Tobacco ,Animals ,Humans ,Apoptosis ,Glycocalyx ,Fibroblast Growth Factor 10 ,Receptors, Fibroblast Growth Factor - Abstract
Background The defects and imbalance in lung repair and structural maintenance contribute to the pathogenesis of chronic obstructive pulmonary diseases (COPD), yet the molecular mechanisms that regulate lung repair process are so far incompletely understood. We hypothesized that cigarette smoking causes glycocalyx impairment and endothelial apoptosis in COPD, which could be repaired by the stimulation of fibroblast growth factor 10 (FGF10)/FGF receptor 1 (FGFR1) signaling. Methods We used immunostaining (immunohistochemical [IHC] and immunofluorescence [IF]) and enzyme-linked immunosorbent assay (ELISA) to detect the levels of glycocalyx components and endothelial apoptosis in animal models and in patients with COPD. We used the murine emphysema model and in vitro studies to determine the protective and reparative role of FGF10/FGFR1. Results Exposure to cigarette smoke caused endothelial glycocalyx impairment and emphysematous changes in murine models and human specimens. Pretreatment of FGF10 attenuated the development of emphysema and the shedding of glycocalyx components induced by CSE in vivo. However, FGF10 did not attenuate the emphysema induced by endothelial-specific killing peptide CGSPGWVRC-GG-D(KLAKLAK)2. Mechanistically, FGF10 alleviated smoke-induced endothelial apoptosis and glycocalyx repair through FGFR1/ERK/SOX9/HS6ST1 signaling in vitro. FGF10 was shown to repair pulmonary glycocalyx injury and endothelial apoptosis, and attenuate smoke-induced COPD through FGFR1 signaling. Conclusions Our results suggest that FGF10 may serve as a potential therapeutic strategy against COPD via endothelial repair and glycocalyx reconstitution.
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- 2022
39. Botulinum Neurotoxin Type A Directly Affects Sebocytes and Modulates Oleic Acid-Induced Lipogenesis
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Karen Brami-Cherrier, Alex Chernavsky, Hui You, Sergei A. Grando, Amy Brideau-Andersen, and Birgitte Sondergaard
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skin ,Botulinum Toxins ,Fibroblast Growth Factor ,Health, Toxicology and Mutagenesis ,5α-dihydrotestosterone ,alpha-dihydrotestosterone ,Receptors, Cell Surface ,Toxicology ,seborrhea ,sebum ,Type A ,BOTOX® ,BOTOX ,Receptors ,Humans ,Botulinum Toxins, Type A ,acne ,Lipogenesis ,Neurosciences ,Pharmacology and Pharmaceutical Sciences ,Foodborne Illness ,Receptors, Fibroblast Growth Factor ,onabotulinumtoxinA ,binding domain ,oiliness ,fibroblast growth factor ,Cell Surface ,Biochemistry and Cell Biology ,Oleic Acid - Abstract
Excess sebum (seborrhea) results in oily skin and is associated with large pore size and acne. Studies in healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations of botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) reduced sebum production, and thus, skin oiliness and pore size. The mechanism for these effects has not been fully elucidated; however, several theories involving direct or indirect effects of BoNT/A on neuronal and/or dermal cells (e.g., sebocytes) have been proposed. In the present study, we evaluated the direct effect of native research grade BoNT/A complex, a commercial preparation of BoNT/A (onabotA), and BoNT/A variants on sebocyte lipogenesis using an in vitro sebocyte cell model. We show that picomolar concentrations of BoNT/A (BoNT/A complex: half maximal effective concentration [EC50] = 24 pM; BoNT/A 150 kDa: EC50 = 34 pM) modulate sebocyte lipogenesis and reduce oleic acid-induced sebocyte differentiation, lipogenesis, and holocrine-like secretion. Comparative studies with the binding domain of BoNT/A, which lacks enzymatic activity, show that this effect is independent of the enzymatic activity of BoNT/A and likely occurs via sebocyte cell surface receptors (e.g., fibroblast growth factor receptors). Overall, these results shed light on the potential mechanism of action and rationale for use of BoNT/A for treatment of sebum-related conditions.
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- 2022
40. Imaging the fibroblast growth factor receptor network on the plasma membrane with DNA-assisted single-molecule super-resolution microscopy
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Yunqing Li, Petra Freund, Johanna V. Rahm, Marie-Lena I. E. Harwardt, Mark S. Schröder, Mike Heilemann, and Marina S. Dietz
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Microscopy ,0303 health sciences ,biology ,Super-resolution microscopy ,Chemistry ,Cell Membrane ,030302 biochemistry & molecular biology ,Cell ,Receptor Protein-Tyrosine Kinases ,Colocalization ,DNA ,Receptors, Fibroblast Growth Factor ,Primary and secondary antibodies ,General Biochemistry, Genetics and Molecular Biology ,Receptor tyrosine kinase ,Cell biology ,Cell membrane ,03 medical and health sciences ,medicine.anatomical_structure ,Membrane protein ,Fibroblast growth factor receptor ,biology.protein ,medicine ,Molecular Biology ,030304 developmental biology - Abstract
Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases and central players in health and disease. Following ligand binding and the formation of homo- and heteromeric complexes, FGFRs initiate a cellular response. Challenges in studying FGFR activation are inner-subfamily interactions and a complex heterogeneity of these in the cell membrane, which demand for observation techniques that can resolve individual protein complexes and that are compatible with endogenous protein levels. Here, we established an imaging and analysis pipeline for multiplexed single-molecule localization microscopy (SMLM) of the FGFR network at the plasma membrane. Using DNA-labeled primary antibodies, we visualize all four FGFRs in the same cell with near-molecular spatial resolution. From the super-resolution imaging data, we extract information on FGFR density, spatial distribution, and inner-subfamily colocalization. Our approach is straightforward and easily adaptable to other multiplexed SMLM data of membrane proteins.
- Published
- 2021
41. Infigratinib Is a Reversible Inhibitor and Mechanism-Based Inactivator of Cytochrome P450 3A4
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Jian Wei Teng, Mei Lin Go, Lloyd Wei Tat Tang, Hao Fan, Ravi Kumar Verma, Eric Chun Yong Chan, Lei Zhou, and Siew Kwan Koh
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Metabolic Clearance Rate ,Reactive intermediate ,Pharmaceutical Science ,Antineoplastic Agents ,Cholangiocarcinoma ,chemistry.chemical_compound ,Non-competitive inhibition ,Humans ,Drug Interactions ,Heme ,Pharmacology ,chemistry.chemical_classification ,CYP3A4 ,biology ,Phenylurea Compounds ,Cytochrome P450 ,Glutathione ,Receptors, Fibroblast Growth Factor ,Pyrimidines ,Enzyme ,Biochemistry ,chemistry ,Catalase ,Inactivation, Metabolic ,biology.protein ,Cytochrome P-450 CYP3A Inhibitors ,Metabolic Networks and Pathways ,NADP - Abstract
Infigratinib (INF) is a promising selective inhibitor of fibroblast growth factor receptors 1-3 that has recently been accorded both orphan drug designation and priority review status by the U.S Food and Drug Administration for the treatment of advanced cholangiocarcinoma. Its propensity to undergo bioactivation to electrophilic species was recently expounded upon. However, other than causing aberrant idiosyncratic toxicities, these reactive intermediates may elicit mechanism-based inactivation (MBI) of cytochrome P450 enzymes (CYP450). In this study, we investigated the interactions between INF and the most abundant hepatic cytochrome P450 3A4 (CYP3A4). Our findings revealed that apart from being a potent noncompetitive reversible inhibitor of CYP3A4, INF inactivated CYP3A4 in a time-, concentration- and NADPH-dependent manner with KI, kinact and partition ratio of 2.45 µM, 0.053 min-1 and 41 respectively when rivaroxaban was employed as the probe substrate. Co-incubation with testosterone (alternative CYP3A substrate) or ketoconazole (direct CYP3A inhibitor) attenuated the rate of inactivation whereas the inclusion of glutathione and catalase did not confer such protection. The lack of enzyme activity recovery following dialysis for 4 hours and oxidation with potassium ferricyanide, coupled with the absence of the characteristic Soret peak signature collectively substantiated that inactivation of CYP3A4 by INF was not mediated by the formation of quasi-irreversible metabolite-intermediate complexes but rather through irreversible covalent adduction to the prosthetic heme and/or apoprotein. Finally, glutathione trapping and high-resolution mass spectrometry experimental results unravelled two plausible bioactivation mechanisms of INF arising from the generation of a p-benzoquinone diimine and epoxide reactive intermediate. Significance Statement The potential of infigratinib (INF) to cause mechanism-based inactivation (MBI) of CYP3A4 was unknown. We report the reversible noncompetitive inhibition and irreversible covalent MBI of CYP3A4 by INF and proposed two potential bioactivation pathways implicating p-benzoquinone diimine and epoxide reactive intermediates. Findings from this study lay the groundwork for future investigation of clinically-relevant drug-drug interactions between INF and concomitant substrates of CYP3A4.
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- 2021
42. Infigratinib: First Approval
- Author
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Connie Kang
- Subjects
medicine.drug_class ,Pharmacology toxicology ,Locally advanced ,Antineoplastic Agents ,Tyrosine-kinase inhibitor ,Food and drug administration ,Cholangiocarcinoma ,Pharmacotherapy ,Medicine ,Humans ,Pharmacology (medical) ,Neoplasm Metastasis ,Receptor, Fibroblast Growth Factor, Type 2 ,Urothelial carcinoma ,business.industry ,United States Food and Drug Administration ,Phenylurea Compounds ,Correction ,Receptors, Fibroblast Growth Factor ,digestive system diseases ,United States ,Pyrimidines ,Fibroblast growth factor receptor ,Cancer research ,AdisInsight Report ,business ,Previously treated - Abstract
Infigratinib (TRUSELTIQTM), a fibroblast growth factor receptor (FGFR)-specific tyrosine kinase inhibitor, is being co-developed by QED Therapeutics and Helsinn for the treatment of cholangiocarcinoma, urothelial carcinoma and other FGFR-driven conditions. Infigratinib was recently approved in the USA for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by a test approved by the US Food and Drug Administration. This article summarizes the milestones in the development of infigratinib leading to this first approval for advanced cholangiocarcinoma. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01567-1.
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- 2021
43. Infigratinib, a Selective Fibroblast Growth Factor Receptor Inhibitor, Suppresses Stent-Induced Tissue Hyperplasia in a Rat Esophageal Model.
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Fu Y, Zhao H, Li J, Li Y, Gong T, An C, Wang R, and Li X
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- Animals, Male, Rats, Hyperplasia etiology, Protein Kinase Inhibitors, Radiography, Rats, Sprague-Dawley, Receptors, Fibroblast Growth Factor, Esophageal Stenosis prevention & control, Stents adverse effects
- Abstract
Purpose: Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model., Methods: Twenty-four male Sprague-Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations., Results: All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05)., Conclusions: Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)
- Published
- 2023
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44. Aberrant acetylated modification of FGF21‑KLB signaling contributes to hepatocellular carcinoma metastasis through the β‑catenin pathway.
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Xia J, Zhu Z, Wen G, Chen Y, An R, Xia S, Guan W, and Ren H
- Subjects
- Humans, beta Catenin genetics, Fibroblast Growth Factors genetics, Receptors, Fibroblast Growth Factor, Cell Movement, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Cell Proliferation, Epithelial-Mesenchymal Transition, Klotho Proteins, Carcinoma, Hepatocellular genetics, Liver Neoplasms genetics
- Abstract
β‑Klotho (KLB) is a vital element of the fibroblast growth factor (FGF) receptor complex and acts as a co‑receptor to facilitate the binding of FGF19 and FGF21 to the FGFRs on the target cells. The present study aimed to determine the contribution of FGF21‑KLB signaling to hepatocellular carcinoma (HCC) metastasis. KLB expression was measured in HCC tissues and cell lines using western blot and reverse transcription‑quantitative PCR. Furthermore, the proliferation, apoptosis and metastasis capacity of KLB‑knockdown Huh7 cells (human HCC cell line) were assessed by Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine assay, flow cytometry, wound‑healing assay and Transwell assay. Enrichment analysis was used to explore the underlying regulatory mechanisms of KLB. The metastasis potential of human HCC cells in the context of FGF21 with or without KLB inhibition was determined in vitro and in vivo . Acetylated modification of KLB was determined using a co‑immunoprecipitation assay. The results indicated a significant upregulation of KLB in HCC tissues compared with the corresponding normal tissues. In addition, KLB expression was closely associated with HCC metastasis. Migration and invasion assays revealed that KLB knockdown promoted the metastatic capability of HCC cells. Gene set variation analysis and subsequent mechanistic investigations revealed that KLB is the upstream regulatory factor of β‑catenin signaling. Furthermore, FGF21 was indicated to suppress HCC metastasis by inhibiting β‑catenin signaling‑driven epithelial‑mesenchymal transition (EMT), while KLB knockdown and simultaneous FGF21 overexpression promoted HCC cell motility. Histone deacetylase 3 (HDAC3) was further characterized as the potential deacetylase for KLB. Furthermore, the results revealed that HDAC3 inhibitor‑mediated acetylated modification led to KLB inactivation, resulting in the blockade of FGF21‑KLB signaling, which further triggered the expression of EMT induction‑related genes in Huh7 cells. In conclusion, the present study demonstrated that aberrant acetylated modification of KLB inhibited FGF21‑KLB signaling, thereby promoting β‑catenin signaling‑driven EMT and HCC metastasis.
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- 2023
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45. The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions.
- Author
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Ahmed SM, Ragunathan P, Shin J, Peter S, Kleissle S, Neuenschwander M, Schäfer R, Kries JPV, Grüber G, and Dröge P
- Subjects
- Adult, Humans, Transcriptional Activation, Chromatin, DNA metabolism, HMGA2 Protein genetics, HMGA2 Protein metabolism, Receptors, Fibroblast Growth Factor, Neoplasms
- Abstract
The architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) is causally involved in several human malignancies and pathologies. HMGA2 is not expressed in most normal adult somatic cells, which renders the protein an attractive drug target. An established cell-based compound library screen identified the fibroblast growth factor receptor (FGFR) inhibitor PD173074 as an antagonist of HMGA2-mediated transcriptional reporter gene activation. We determined that PD173074 binds the C-terminus of HMGA2 and interferes with functional coordination of the three AT-hook DNA-binding domains mediated by the C-terminus. The HMGA2-antagonistic effect of PD173074 on transcriptional activation may therefore result from an induced altered DNA-binding mode of HMGA2. PD173074 as a novel HMGA2-specific antagonist could trigger the development of derivates with enhanced attributes and clinical potential., (© 2023 Federation of European Biochemical Societies.)
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- 2023
- Full Text
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46. Discovery and Structural Optimization of Novel Quinolone Derivatives as Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors.
- Author
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Hu S, Liu Y, Ma J, Ding W, Chen H, Jiang H, Chen H, Wei S, Liu Y, Jin Q, Yuan H, and Yan L
- Subjects
- Humans, Mice, Animals, Receptors, Fibroblast Growth Factor, Molecular Docking Simulation, Chromatography, Liquid, Structure-Activity Relationship, Tandem Mass Spectrometry, Receptor, Fibroblast Growth Factor, Type 1, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors chemistry, Cell Line, Tumor, Quinolones pharmacology, Quinolones therapeutic use, Carcinoma, Hepatocellular, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Liver Neoplasms
- Abstract
Aberrant activation of fibroblast growth factor receptors (FGFRs) has been identified as an oncogenic driver force for multiple cancer types, making FGFRs a compelling target for anticancer therapy. Because of the renewed interest in irreversible inhibitors, considerable efforts have been made to find irreversible FGFR inhibitors. Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound ( lenvatinib ) under the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR 1-4 with nanomolar activity and effectively suppressed the proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed high selectivity against a panel of 369 kinases at 1 μM. The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.
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- 2023
- Full Text
- View/download PDF
47. Expression of fibroblast growth factor receptor substrate 2 (FRS2) in primary retroperitoneal liposarcoma and its clinical implications.
- Author
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Chen WD and Miao CL
- Subjects
- Humans, Retrospective Studies, Prognosis, Receptors, Fibroblast Growth Factor, Neoplasm Recurrence, Local pathology, Membrane Proteins, Adaptor Proteins, Signal Transducing, Liposarcoma surgery, Liposarcoma pathology
- Abstract
Objective: The aim of this study was to investigate the expression level of fibroblast growth factor receptor substrate 2 (FRS2) in tissues of patients with primary retroperitoneal liposarcoma (PRPLS) and its correlation with recurrence and prognosis., Patients and Methods: The pathological specimens, medical records, and follow-up information of patients with PRPLS who underwent radical surgery for the first time in our hospital from January 2013 to December 2016 were retrospectively analyzed. FRS2 protein expression in tissues was determined by immunohistochemistry staining, and the FRS2 protein positive rates in patients with different clinicopathological features were compared. Factors influencing patients' recurrence and survival were determined using the multivariate Cox stepwise regression model., Results: This research enrolled 87 patients with PRPLS, with the number of cases presenting FRS2 protein positive rate and positive rate in pathological tissues accounting for 62.07% (54/87) and 37.93% (33/87), respectively. The positive expression of FRS2 protein varied markedly among patients with different pathological types, FNCC, LCC grade, number of tumors, positive margin, and recurrence and metastasis (with vs. without) (all p<0.05). The 87 patients were followed up for 3.5-102 months (median, 27.5 months), with a postoperative 5-year overall disease-free survival (DFS) rate of 17.24% [median progression-free survival (PFS): 24.7 months] and a 5-year overall survival (OS) rate of 44.83% (median OS: 47.3 months). Kaplan-Meier survival curves revealed significantly shorter PFS and OS in patients with positive FRS2 protein expression vs. those with negative FRS2 protein expression (χ2=6.396, 5.032, p<0.05). According to the univariate analysis, the 5-year overall DFS rate varied significantly among patients with different pathological types, Fédération Nationale des Centres De Lutte Contre le Cancer (FNCLCC) grades, number of tumors, positive margin, and FRS2 protein expression (all p<0.05). Pathological type, FNCLCC grading, tumor number, recurrence and metastasis, positive margin, and FRS2 protein expression were significantly correlated with the 5-year OS rate of patients (all p<0.05). Furthermore, pathological type, FNCLCC grading, multiple tumors, positive margin, and FRS2 protein expression were identified by multivariate Cox regression analysis to be independent factors that affected patients' 5-year DFS and OS rates (all p<0.05), and that relapsed and metastasized patients had a 4.586-fold risk of death than those without recurrence and metastasis., Conclusions: FRS2 shows a high positive rate in the tissues of PRPLS patients and is significantly related to the prognostic recurrence and survival of patients, with potential value in judging the prognosis of patients.
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- 2023
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48. Fibroblast growth factor 23, klotho and heparin.
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Thomas SM, Li Q, and Faul C
- Subjects
- Humans, Fibroblast Growth Factors metabolism, Glucuronidase metabolism, Heparin, Receptors, Fibroblast Growth Factor, Animals, Fibroblast Growth Factor-23, Renal Insufficiency, Chronic metabolism
- Abstract
Purpose of Review: Fibroblast growth factor (FGF) 23 is a bone-derived hormone that regulates phosphate and vitamin D metabolism by targeting the kidney. When highly elevated, such as in chronic kidney disease (CKD), FGF23 can also target the heart and induce pathologic remodeling. Here we discuss the mechanisms that underlie the physiologic and pathologic actions of FGF23, with focus on its FGF receptors (FGFR) and co-receptors., Recent Findings: Klotho is a transmembrane protein that acts as an FGFR co-receptor for FGF23 on physiologic target cells. Klotho also exists as a circulating variant, and recent studies suggested that soluble klotho (sKL) can mediate FGF23 effects in cells that do not express klotho. Furthermore, it has been assumed that the actions of FGF23 do not require heparan sulfate (HS), a proteoglycan that acts as a co-receptor for other FGF isoforms. However, recent studies revealed that HS can be part of the FGF23:FGFR signaling complex and modulate FGF23-induced effects., Summary: sKL and HS have appeared as circulating FGFR co-receptors that modulate the actions of FGF23. Experimental studies suggest that sKL protects from and HS accelerates CKD-associated heart injury. However, the in vivo relevance of these findings is still speculative., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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49. Autoantibodies Against Trisulfated Heparin Disaccharide and Fibroblast Growth Factor Receptor-3 May Play a Role in the Pathogenesis of Neuropathic Corneal Pain.
- Author
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Bayraktutar BN, Atocha V, Farhad K, Soto O, and Hamrah P
- Subjects
- Adult, Female, Humans, Male, Autoantibodies, Cornea innervation, Immunoglobulin M, Neuralgia etiology, Receptors, Fibroblast Growth Factor, Small Fiber Neuropathy etiology, Small Fiber Neuropathy pathology
- Abstract
Purpose: The aim of this study was to describe cases of patients with presumable dysimmune small-fiber neuropathy (SFN)-related neuropathic corneal pain (NCP), presenting with autoantibodies against trisulfated heparin disaccharide (TS-HDS) or fibroblast growth factor receptor-3 (FGFR-3)., Methods: This study was a case series of 3 patients with NCP with positive anti-TS-HDS and/or anti-FGFR-3 autoantibodies and systemic SFN as confirmed by positive skin biopsy results., Results: All 3 patients were women with a mean age of 34.3± 6.1 years. They suffered from moderate to severe persistent chronic ocular discomfort (10/10, 10/10, and 9/10 on a visual analogue scale, respectively). Although 1 patient suffered from ocular pain and photophobia alone, the other 2 patients experienced additional non-ocular pain. One of the patients had pain on her face and head, and 1 patient reported neck and lower back pain. Two patients had high anti-TS-HDS IgM titers, whereas 1 patient had both high anti-TS-HDS IgM and anti-FGFR-3 IgG titers. Skin biopsy confirmed the presence of SFN in all patients by demonstrating decreased intraepidermal nerve fiber density., Conclusions: The presence of anti-TS-HDS and anti-FGFR-3 autoantibodies in patients with NCP with positive skin biopsy findings for SFN highlights the potential role of dysimmune SFN in the pathogenesis of this disease., Competing Interests: Conflicts of interest statement: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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50. Osteocytes and the pathogenesis of hypophosphatemic rickets
- Author
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Miwa, Yamazaki and Toshimi, Michigami
- Subjects
Extracellular Matrix Proteins ,Endocrinology, Diabetes and Metabolism ,Calcium-Binding Proteins ,Phosphorus ,Osteocytes ,Receptors, Fibroblast Growth Factor ,Phosphates ,Rickets, Hypophosphatemic ,Fibroblast Growth Factors ,Mice ,Endopeptidases ,Animals ,Familial Hypophosphatemic Rickets ,Hydroxyapatites ,beta Catenin - Abstract
Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for maintaining phosphate homeostasis and is mainly produced by osteocytes. FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys. Osteocytes are cells of osteoblastic lineage that have undergone terminal differentiation and become embedded in mineralized bone matrix. Osteocytes express FGF23 and other multiple genes responsible for hereditary hypophosphatemic rickets, which include phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C (FAM20C). Since inactivating mutations in PHEX, DMP1, and FAM20C boost the production of FGF23, these molecules might be considered as local negative regulators of FGF23. Mouse studies have suggested that enhanced FGF receptor (FGFR) signaling is involved in the overproduction of FGF23 in PHEX-deficient X-linked hypophosphatemic rickets (XLH) and DMP1-deficient autosomal recessive hypophosphatemic rickets type 1. Since FGFR is involved in the transduction of signals evoked by extracellular Pi, Pi sensing in osteocytes may be abnormal in these diseases. Serum levels of sclerostin, an inhibitor Wnt/β-catenin signaling secreted by osteocytes, are increased in XLH patients, and mouse studies have suggested the potential of inhibiting sclerostin as a new therapeutic option for the disease. The elucidation of complex abnormalities in the osteocytes of FGF23-related hypophosphatemic diseases will provide a more detailed understanding of their pathogenesis and more effective treatments.
- Published
- 2022
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