Search

Background: Although selpercatinib has shown clinical benefits for rearranged during transfection (RET) fusion–positive non-small cell lung cancer (NSCLC), its cost-effectiveness requires further evaluation. Aim: This study aimed to evaluate the cost-effectiveness of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of RET fusion–positive NSCLC from the perspective of the United States (US) payer. Method: A partitioned survival model was developed based on data from the LIBRETTO-431 trial. Cost and utility values for the health state were obtained from database data or published literature. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analyses (PSA) were conducted to assess the uncertainty of the model. Results: Selpercatinib increased QALYs in patients with RET fusion–positive NSCLC by 0.90 compared to chemotherapy plus pembrolizumab, with an additional cost of $542,517.45, resulting in an ICER of $603,286.49/QALY, which exceeded the willingness-to-pay (WTP) threshold ($150,000) in the US. One-way sensitivity analysis suggested that the utility of progressed disease, the utility of progression-free survival, the price of selpercatinib, the discount, the price of pemetrexed, and the price of pembrolizumab had the greatest influence on the cost- effectiveness analysis process. In the PSA, 99.9% of the scatter points were distributed above the US WTP threshold of $150,000. Conclusion: From the perspective of the US payer, selpercatinib is not cost-effective compared to chemotherapy and pembrolizumab for first-line treatment in patients with RET fusion-positive NSCLC. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China′s clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians. [ABSTRACT FROM AUTHOR]

Combined small cell lung cancer (C-SCLC) is a relatively rare subtype of small cell lung cancer (SCLC) which combines SCLC and any component of non-small cell carcinoma (NSCLC). Patients diagnosed with C-SCLC are currently recommended to receive the same treatment as SCLC cases in the absence of clear evidence suggesting different strategies. The genomic profiling of C-SCLC is rarely studied. Herein, we report a case of extensive-stage C-SCLC harboring the KIF5B-RET fusion before first-line therapy and with persistent sensitivity to fourth-line selpercatinib treatment is reported.Materials and Methods: Molecular and pathological features were evaluated using transbronchial lung biopsy, immunohistochemical (IHC) staining and next-generation sequencing (NGS).Results: NGS revealed the KIF5B-RET fusion in the C-SCLC tumor. The patient had a progression-free survival (PFS) surpassing 14 months after selpercatinib treatment, with ongoing clinical response in 4th-line treatment.Conclusion: This case highlights the importance of comprehensive molecular testing in C-SCLC for selecting the optimal treatment. Although RET fusion is rare in patients with C-SCLC, its identification and treatment with selective RET inhibitors may contribute to clinical benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: Lately, a more personalized approach in the management of advanced thyroid cancer patients has improved the outcomes, and several novel molecularly guided therapies, including selective RET inhibitors (sRETis), have demonstrated promising efficacy in clinical trials. RET (rearranged during transfection) variants are the most prevalent oncogenic event in medullary thyroid cancer (MTC). We here found RET oncogene variants in 44/48 prospectively collected MTC tumor samples from patients treated with more unselective kinase inhibitors vandetanib and/or cabozantinib. Our study shows that RET variants were highly prevalent in patients with advanced MTC, and the treatment results in RET-positive cases were similar to those reported in unselected cohorts. Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts. [ABSTRACT FROM AUTHOR]

Objective: Rearranged during transfection genes are present in 1−2% of patients who have non-small cell lung cancer and 10−30% of patients with papillary thyroid cancer. The objective of this article is to review the current rearranged during transfection inhibitors indicated for patients with rearranged during transfection-mutated cancers and their future directions. Data sources: The pivotal phase I/II studies for selpercatinib and pralsetinib were evaluated. Current studies on rearranged during transfection inhibitors were searched on ClinicalTrials.gov using the key word "RET." Data summary: Selpercatinib and pralsetinib were the first two U.S. Food and Drug Administration-approved rearranged during transfection-selective inhibitors for advanced or metastatic rearranged during transfection fusion-positive non-small cell lung cancer, rearranged during transfection-mutant medullary thyroid cancer, and rearranged during transfection fusion-positive thyroid cancer. Both agents showed promising efficacy with objective response rate ranging from 60% to 73% in all aforementioned rearranged during transfection-mutated cancers. Additionally, benefits were seen even in patients with intracranial metastasis at baseline. Both showed favorable safety profiles. Some common class adverse events included elevated liver function tests and hypertension. Hematologic side effects such as anemia and neutropenia were more common with pralsetinib. Selpercatinib had interactions with acid suppressive therapy and specific instructions when used concomitantly. Conclusions: While the rearranged during transfection inhibitors are generally well-tolerated, each agent possesses slightly different efficacy, side-effect profile, and drug−drug interactions. [ABSTRACT FROM AUTHOR]

Abstract Background Hirschsprung disease, the most important congenital colonic dysmotility in children results from neural crest migration, differentiation, proliferation, or apoptosis defects where the rearranged during transfection (RET)-Protooncogene pathway has a central role. Although palatal and retinal anomalies in the context of chromosomopathies and some mono−/oligogenic syndromes are reported associated with Hirschsprung disease the role of inactivating RET mutations in these cases is not clarified. Case presentation We report on a dysmorphic newborn with cleft palate and palatal synechia, who showed intestinal obstruction after 24 h of life. Transient ileostomy and surgical biopsies were performed to diagnose aganglionosis of the colon and last ileal loop. No chromosomal anomalies or copy number variations were found. We identified a paternal heterozygous germline mutation c.1852 T > C, which results in the substitution of cysteine by arginine in the RET-receptor tyrosine kinase (p.C618R mutation). There was no family history of Hirschsprung disease, but the father underwent surgery for medullary thyroid carcinoma and was affected by retinal dystrophy. Conclusions The occurrence of Hirschsprung disease and carcinoma shows how a single mutation may be responsible for adverse effects: gain and loss of function of the same receptor. Furthermore, it would be interesting to study its dual role in face and retina embryology, and to extend targeted investigations of RET hotspots in these developmental abnormalities to facilitate counselling, follow-up, and tumor prevention. Complex surgical procedures and genetic testing as well as socio-economic impact are a challenge for familiar compliance.

Background: REarranged during Transfection (RET) gene fusion is one of the common oncogenic variants detectable in non-small cell lung cancer (NSCLC). The feature of most oncogenic RET gene fusion cases is that RET tyrosine kinase domain is retained in fusions and the partner gene includes a coiled-coil or LIS1 homology domain. However, only a few studies reported about the exceptional form of RET fusion in NSCLC so far. Methods: Targeted next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) were performed on resected cancerous tissue. Results: A rare form of RET fusion was identified in a 45 year-old Chinese female patient, in which exon 1–4 of LDLR fused with exon 12–21 of RET. The result was validated by FISH. Conclusions: This novel form of RET fusion in NSCLC is reported for the first time worldwide, offering a new treatment option for the patient with the possibility of using RET-selective inhibitors. [ABSTRACT FROM AUTHOR]

Jes Sloth Mathiesen,1,2 Jens Peter Kroustrup,3 Peter Vestergaard,3,4 Kirstine Stochholm,5,6 Per Løgstrup Poulsen,6 Åse Krogh Rasmussen,7 Ulla Feldt-Rasmussen,7 Sten Schytte,8 Stefano Christian Londero,8 Henrik Baymler Pedersen,9 Christoffer Holst Hahn,10 Jens Bentzen,11 Sören Möller,2,12 Mette Gaustadnes,13 Maria Rossing,14 Finn Cilius Nielsen,14 Kim Brixen,2 Anja Lisbeth Frederiksen,2,15 Christian Godballe1 On behalf of the Danish Thyroid Cancer Group (DATHYRCA) 1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 4Steno Diabetes Center North Jutland, Aalborg, Denmark; 5Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark; 6Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark; 7Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark; 8Department of ORL Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark; 9Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark; 10Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark; 11Department of Oncology, Herlev Hospital, Herlev, Denmark; 12Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 13Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 14Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark; 15Department of Clinical Genetics, Odense University Hospital, Odense, Denmark Background: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested.Methods: The study included 200 patients identified from the nationwide Danish MTC cohort 1997–2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994–2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested.Results: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81–0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76–0.88; 131/158). Completeness was 88% (95% CI: 0.75–0.95; 42/48) and 81% (95% CI: 0.72–0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested.Conclusion: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test. Keywords: RET testing, medullary thyroid carcinoma, Denmark

Medullary thyroid carcinoma is a rare neuroendocrine tumor arising from parafollicular cells of the thyroid gland. It occurs in both hereditary and sporadic forms which are associated with the gain of function mutations in rearranged during transfection proto-oncogene on chromosome 10q11.2. There are various syndromic and sporadic clinical presentations, and the understanding of the molecular pathophysiology and its genotype–phenotype correlation has led to mutation-based risk stratification and guidelines for evaluation and management. The authors present a current review of the literature with regard to pathophysiology, molecular basis, clinical presentation along with genotype–phenotype correlation and guidelines for evaluation and management.

Background: Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants.Methods: This study was a retrospective case comparison study of all MEN 2A index patients (n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively.Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability.Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.

• RET51 isoform interacts with scaffold protein Ezrin and Src in lung cancer cells. • RET-Src-Ezrin signaling mediates activation of RhoA and ROCK1/2. • Enhanced RET signaling promotes cytoskeletal reorganization for chemotaxis. • RET-Ezrin signaling drives lung cancer metastasis. • RET and Ezrin selective inhibitors present unique options for treating lung cancer. Increased expression of REarranged during Transfection (RET) kinase is reported in 10–20 % of lung adenocarcinomas (LUAD) and is associated with metastasis and reduced survival. Ezrin is a scaffold protein that promotes protein interactions with the actin cytoskeleton to regulate cell migration and is also associated with invasion and metastasis in cancers. RET isoforms interact with unique combinations of scaffold proteins to promote distinct signaling pathways. We hypothesized that RET isoforms associate distinctly with Ezrin for cytoskeletal reorganization and LUAD cell migration processes. HCC1833 and A549 LUAD, SH-SY5Y neuroblastoma or HEK-293 cells expressing RET and Ezrin were stimulated with the RET ligand glial cell line-derived neurotrophic factor (GDNF) and treated with RET, Ezrin or Src inhibitors. Co-immunoprecipitation or pull-down assays coupled to immunoblotting were used to investigate protein activation and interactions. Immunofluorescence confocal microscopy assessed LUAD cytoskeletal reorganization and colocalization of RET and Ezrin. Live-cell fluorescence imaging was used to measure cell migration and chemotaxis. GDNF promoted activation, interaction and colocalization of RET51 isoform and Ezrin. Inhibition of RET or Src impaired Ezrin interactions with RET and Src. GDNF stimulation enhanced the formation of actin-rich filopodia, in which both RET and Ezrin were enriched, and promoted chemotaxis in LUAD cells. However, inhibition of RET, Src or Ezrin suppressed filopodia formation, reduced colocalization of Ezrin with RET, and impaired cell migration and/ or chemotaxis. We further showed that GDNF-mediated activation of RET and Ezrin promoted RhoA-GTPase activity and signaling of ROCK1 and ROCK2 in LUAD cells. Expression and activation of RET51 mediates unique protein interactions with Ezrin to promote LUAD cell chemotaxis for cancer cell dissemination, which may have implications in LUAD metastatic progression. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.

Chronic kidney disease is estimated to affect approximately 10 to 15% of the Chinese population. Renal fibrosis is characterized by progressive extracellular matrix deposition in the kidney parenchyma with eventual tissue scarring and inevitable deterioration of renal function. Vascular rarefaction, glomerulosclerosis, interstitial inflammation, and fibrogenesis are associated with or contribute to renal fibrosis. Recent studies have revealed that glial cell-derived neurotrophic factor (GDNF) is involved in kidney morphogenesis and amelioration of renal injury. Ideal therapies targeting the pathogenesis of renal fibrosis should have the potential to inhibit glomerular and tubulointerstitial fibrosis by targeting multiple pathological events. GDNF plays a unique role in both renal development and improvement of renal fibrosis, and GDNF kidney receptors and signaling pathways can ameliorate renal apoptosis and inflammation. Our work contributes to the establishment of GDNF as an emerging therapy that can increase the effectiveness of currently used interventions to improve renal fibrosis. This literature review focuses on the important role of GDNF in renal development and its relationship with renal fibrosis.

Objective: To explore the neuroprotective effects of electroacupuncture (EA) on hypoxic-ischemic encephalopathy (HIE) and to further investigate the role of glial cell line-derived neurotrophic factor (GDNF) family receptor member RET (rearranged during transfection) and its key downstream phosphatidylinositol 3 kinase (PI-3K)/protein kinase B (Akt) pathway in the process. Methods: A total of 220 seven-day-old SD rats (of either sex, from 22 broods) were randomly divided into two groups, one (30 rats) for sham-surgery group and the other (190 rats) for HIE model group. The HIE model was established using the left common carotid artery ligation method in combination with hypoxic treatment. The successfully established rats were randomly divided into five groups, including control model group, EA group, sham-EA group, antagonist group and antagonist plus electroacupuncture group, with 35 rats in each group. Baihui (GV 20), Dazhui (GV 14), Quchi (LI 11) and Yongquan (KI 1) acupoints were chosen for acupuncture. EA was performed at Baihui and Quchi for 10 min once a day for continuous 1, 3, 7 and 21 days, respectively. The rats were then killed after the operation and injured cerebral cortex was taken for the measurement of neurologic damage by hematoxylin-eosin (HE) staining and the degenerative changes of cortical ultrastructure by transmission electron microscopy. RET mRNA level and Akt protein level were detected by real-time reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively. Results: EA could ameliorate neurologic damage of the first somatic sensory area (S1Tr) and alleviate the degenerative changes of ultrastructure of cortical neurons in rats subjected to HIE. And the longer acupuncture treatment lasted, the better its therapeutic effect would be. This was accompanied by gradually increased expression of GDNF family receptor RET at the mRNA level and its downstream signaling Akt at the protein level in the ischemic cortex. Conclusion: EA has neuroprotective effects on HIE and could be a potential therapeutic strategy for HIE in the neonate. Activation of RET/Akt signaling pathway might be involved in this process. [ABSTRACT FROM AUTHOR]

Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for greater than 80% of cases. Surgical resection, with or without postoperative radioiodine therapy, remains the standard of care for patients with PTC, and the prognosis is generally excellent with appropriate treatment. Despite this, significant numbers of patients will not respond to maximal surgical and medical therapy and ultimately will die from the disease. This mortality reflects an incomplete understanding of the oncogenic mechanisms that initiate, drive, and promote PTC. Nonetheless, significant insights into the pathologic subcellular events underlying PTC have been discovered over the last 2 decades, and this remains an area of significant research interest. Chromosomal rearrangements resulting in the expression of fusion proteins that involve the rearranged during transfection (RET) proto-oncogene were the first oncogenic events to be identified in PTC. Members of this fusion protein family (the RET/PTC family) appear to play an oncogenic role in approximately 20% of PTCs. Herein, the authors review the current understanding of the clinicopathologic role of RET/PTC fusion proteins in PTC development and progression and the molecular mechanisms by which RET/PTCs exert their oncogenic effects on the thyroid epithelium. [ABSTRACT FROM AUTHOR]

We report a case of a 29-year-old female with the family history of medullary thyroid carcinoma (MTC) presenting with hematuria and tachycardia, who was found to have bilateral adrenal masses on abdominal computed tomography and biochemical testing compatible with pheochromocytoma. Iodine-123 (I-123) metaiodobenzylguanidine (MIBG) scintigraphy for preoperative planning prior to planned adrenalectomy revealed incidental synchronous unifocal MTC, along with expected bilateral adrenal pheochromocytomas. Pathology confirmed these findings, and subsequent genetic testing confirmed a rearranged during transfection proto-oncogene mutation on exon 11, confirming the clinical diagnosis of multiple endocrine neoplasia 2A (MEN 2A). The unexpected incidental finding of synchronous MTC highlights the importance of considering MEN in the differential diagnosis when encountered with newly diagnosed pheochromocytoma and highlights the utility of I-123 MIBG scintigraphy in diagnostic workup of newly diagnosed pheochromocytoma. [ABSTRACT FROM AUTHOR]

Cancer cells rewire their metabolism to meet the demands of growth and survival and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. However, the respective mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of glioma are unclear. The present study demonstrated that glial‑derived neurotrophic factor (GDNF) is highly expressed in glioma and associated with poor clinical outcomes. In addition, there was a significant correlation between GDNF/rearranged during transfection (RET)/ERK signaling and sterol regulatory element‑binding protein‑1 (SREBP‑1) expression in glioma cells. Pharmacological or genetic inhibition of GDNF‑induced RET/ERK activity downregulated SREBP‑1 expression and SREBP‑1‑mediated transcription of lipogenic genes. Additionally, GDNF regulated SREBP‑1 activity by promoting hypoxia‑inducible factor‑1α (HIF‑1α) mediated glucose absorption and hexosamine biosynthetic pathway mediated SREBP cleavage‑activating protein N‑glycosylation. In addition, the inhibition of SREBP‑1 reduced the in vitro GDNF‑induced glioma cell proliferation. The results elucidated the complex relationship between GDNF/RET/ERK signaling and dysregulated glycolipid‑metabolism, which shows great potential to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

REarranged during Transfection (RET) gene encodes a receptor tyrosine kinase and it was initially discovered as an in vitro transforming gene. For many years, RET has been involved in papillary thyroid carcinoma and medullary thyroid carcinoma. More recently, lung adenocarcinoma and chronic myelomonocytic leukemia samples have been found to display RET gene rearrangements. This knowledge is stimulating the search for protein kinase inhibitors to combat RET-driven malignancies. [ABSTRACT FROM AUTHOR]

The rearranged during transfection/papillary thyroid carcinoma (RET/PTC) tyrosine kinase is an oncogene implicated in the tumorigenesis of thyroid cancer. Recent studies by us and others have shown that RET/PTC kinase expression is induced by estrogen in breast cancer cells. Due to the critical involvement of estrogen-regulated genes in the pathogenesis of breast cancer, we investigated the expression, regulation, and function of RET/PTC kinase in breast cancer cells. We found that RET/PTC kinase expression correlates with estrogen receptor (ER) expression in breast cancer cells and tumor specimens, and that RET/PTC kinase expression is associated with a poor prognosis in ER-positive breast cancer patients. We found that estrogen rapidly induces RET/PTC kinase expression in an ER-dependent manner in breast cancer cells and that this induction is through a transcriptional regulatory mechanism. Using reporter assays, small interfering RNA (siRNA) assays, and chromatin immunoprecipitation (ChIP) assays, we demonstrated the necessity of crosstalk between ER and the forkhead box A1 (FOXA1) transcription factor in regulating RET/PTC kinase expression. In functional studies, increased expression of RET/PTC kinase induced by estrogen stimulation resulted in elevated phosphorylation of multiple downstream kinase signaling pathways. Conversely, knockdown of RET/PTC expression was associated with the inhibition of these same kinase signaling pathways, and, in fact, decreased the stimulatory effect of estrogen on the proliferation of ER-positive breast cancer cells. These results demonstrate a novel pathway of ER and FOXA1 transcription factor crosstalk in regulating RET/PTC kinase expression, and demonstrate that RET/PTC kinase is a critical regulator for the proliferation of ER-positive breast cancer cells. Taken together, our study suggests that RET/PTC kinase may serve as a novel prognostic biomarker and therapeutic target for prevention and treatment of ER-positive breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: In addition to their established functions in programmed cell death, there is increasing evidence that caspases contribute to several other cellular processes beside of apoptosis. So-called “dependence receptors” represent a group of receptors, which derive from different protein families, but are functionally linked by their capability to regulate cell survival in presence of their respective ligands thereby preserving cellular homeostasis. In the absence of their ligands these receptors are cleaved by caspases thereby releasing pro-apoptotic receptor fragments (e.g. rearranged during transfection [RET]) or permitting the exposure of death domains, which were masked before through other receptor domains (e.g. deleted in colorectal carcinoma [DCC]). Apart from these, there are other plasma membrane receptors such as the epidermal growth factor receptor, which have been identified as substrates of caspases. In terms of signal-transduction, caspase-mediated cleavage of these receptors blocks ligand-induced activation of their intracellular signalling. It is hypothesized that this might be another mechanism, whereby caspases trigger cell toxicity through shut-down of survival signals. [Copyright &y& Elsevier]