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BACKGROUND: This work aims to explore the anticancer potential of compounds isolated from Heterophragma adenophyllum (H. adenophyl-lum) leaves and investigate their molecular interactions with cancer-related targets. H. adenophyllum, a plant with potential medicinal properties, offers a promising avenue for such investigations. METHODs: The study involved the extraction and isolation of compounds from H. adenophyllum leaves, followed by an evaluation of their cytotoxicity against U87 malignant glioma cell lines. U87 malignant glioma cell lines were exposed to different concentrations of the compounds for cytotoxicity. The inhibitory effect on cell growth was analyzed, and IC50 values were determined. Additionally, molecular docking studies were conducted to investigate the interactions of the compounds with two important cancer-related targets, the X-ray crystal structure of duplex DNA and epidermal growth factor receptor (EGFR). RESULTS: The cytotoxicity evaluation demonstrated dose-dependent inhibition of cell growth by the isolated compounds. Peshawaraqui- none (pesh-quinone) exhibited the highest cytotoxicity, with an IC50 value of 87.9 ^M. The indanone derivatives (Ind), lapachol (Lappa), and a-lapachone (Alpha Lappa) showed IC50 values of 174.9 ^M, 141.4 ^M, and 132.8 ^M, respectively. In the molecular docking studies, the com-pounds displayed significant interactions with key residues within the active sites of the duplex DNA and EGFR proteins, suggesting potential binding affinity and therapeutic relevance. CONCLUsiONs: Results of this work shoes that compounds isolated from H. adenophyllum leaves possess significant anticancer potential. The observed cytotoxic effects against U87 malignant glioma cells and the molecular interactions with cancer-related targets further support the promise of these compounds as potential anticancer agents. [ABSTRACT FROM AUTHOR]

Purpose GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). Materials and Methods Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/wk) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. Results RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of = grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0 to 8.0). Conclusion GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC. [ABSTRACT FROM AUTHOR]

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Background: To establish a predictive model based on multisequence magnetic resonance imaging (MRI) using deep learning to identify wild-type (WT) epidermal growth factor receptor (EGFR), EGFR exon 19 deletion (19Del), and EGFR exon 21-point mutation (21L858R) simultaneously. Methods: A total of 399 patients with proven brain metastases of non-small cell lung cancer (NSCLC) were retrospectively enrolled and divided into training (n = 306) and testing (n = 93) cohorts separately based on two timepoints. All patients underwent 3.0-T brain MRI including T2-weighted, T2-weighted fluid-attenuated inversion recovery, diffusion-weighted imaging, and contrast-enhanced T1-weighted sequences. Radiomics features were extracted from each lesion based on four sequences. An algorithm combining radiomics approach with graph convolutional networks architecture (Radio-GCN) was designed for the prediction of EGFR mutation status and subtype. The area under the curve (AUC) at receiver operating characteristic analysis was used to evaluate the predication capabilities of each model. Results: We extracted 1,290 radiomics features from each MRI sequence. The AUCs of the Radio-GCN model for identifying EGFR 19Del, 21L858R, and WT for the lesion-wise analysis were 0.996 ± 0.004, 0.971 ± 0.013, and 1.000 ± 0.000 on the independent testing cohort separately. It also yielded AUCs of 1.000 ± 0.000, 0.991 ± 0.009, and 1.000 ± 0.000 for predicting EGFR mutations respectively for the patient-wise analysis. The κ coefficients were 0.735 and 0.812, respectively. Conclusions: The constructed Radio-GCN model is a new potential tool to predict the EGFR mutation status and subtype in NSCLC patients with brain metastases. Relevance statement: The study demonstrated that a deep learning approach based on multisequence MRI can help to predict the EGFR mutation status in NSCLC patients with brain metastases, which is beneficial to guide a personalized treatment. Key points: • This is the first study to predict the EGFR mutation subtype simultaneously. • The Radio-GCN model holds the potential to be used as a diagnostic tool. • This study provides an imaging surrogate for identifying the EGFR mutation subtype. [ABSTRACT FROM AUTHOR]

The activation of members of the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and have profound consequences both in physiological and pathological conditions. Within the nervous system, the neuregulin (NRG)/ErbB3 signaling plays a crucial role in promoting the formation and maturation of excitatory synapses. Noteworthy is ErbB3, which is actively involved in the process of cerebellar lamination and myelination. All members of the ErbB-family, in particular ErbB3, have been observed within the nuclei of various cell types, including both full-length receptors and alternative variants. One of these variants was detected in Schwann cells and in glioblastoma primary cells where it showed a neuregulin-dependent expression. It binds to promoters' chromatin associated with genes, like ezrin, involved in the formation of Ranvier's node. Its nucleolar localization suggests that it may play a role in ribosome biogenesis and in cell proliferation. The regulation of ErbB3 expression is a complex and dynamic process that can be influenced by different factors, including miRNAs. This mechanism appears to play a significant role in glioblastoma and is often associated with a poor prognosis. Altogether, the targeting of ErbB3 has emerged as an active area of research in glioblastoma treatment. These findings highlight the underappreciated role of ErbB3 as a significant receptor that can potentially play a pivotal role in diverse pathologies, implying the existence of a shared and intricate mechanism that warrants further investigation. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/β-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors. [ABSTRACT FROM AUTHOR]

Background: To evaluate the value of computed tomography (CT) radiomics in predicting the risk of developing epidermal growth factor receptor (EGFR) T790M resistance mutation for metastatic non-small lung cancer (NSCLC) patients before first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs) therapy. Methods: A total of 162 metastatic NSCLC patients were recruited and split into training and testing cohort. Radiomics features were extracted from tumor lesions on nonenhanced CT (NECT) and contrast-enhanced CT (CECT). Radiomics score (rad-score) of two CT scans was calculated respectively. A nomogram combining two CT scans was developed to evaluate T790M resistance within up to 14 months. Patients were followed up to calculate the time of T790M occurrence. Models were evaluated by area under the curve at receiver operating characteristic analysis (ROC-AUC), calibration curve, and decision curve analysis (DCA). The association of the nomogram with the time of T790M occurrence was evaluated by Kaplan–Meier survival analysis. Results: The nomogram constructed with the rad-score of NECT and CECT for predicting T790M resistance within 14 months achieved the highest ROC-AUCs of 0.828 and 0.853 in training and testing cohorts, respectively. The DCA showed that the nomogram was clinically useful. The Kaplan–Meier analysis showed that the occurrence time of T790M difference between the high- and low-risk groups distinguished by the rad-score was significant (p < 0.001). Conclusions: The CT-based radiomics signature may provide prognostic information and improve pretreatment risk stratification in EGFR NSCLC patients before EGFR-TKIs therapy. The multimodal radiomics nomogram further improved the capability. Relevance statement: Radiomics based on NECT and CECT images can effectively identify and stratify the risk of T790M resistance before the first-line TKIs treatment in metastatic non-small cell lung cancer patients. Key points: • Early identification of the risk of T790M resistance before TKIs treatment is clinically relevant. • Multimodel radiomics nomogram holds potential to be a diagnostic tool. • It provided an imaging surrogate for identifying the pretreatment risk of T790M. [ABSTRACT FROM AUTHOR]

Background: To evaluate the value of computed tomography (CT) radiomics in predicting the risk of developing epidermal growth factor receptor (EGFR) T790M resistance mutation for metastatic non-small lung cancer (NSCLC) patients before first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs) therapy. Methods: A total of 162 metastatic NSCLC patients were recruited and split into training and testing cohort. Radiomics features were extracted from tumor lesions on nonenhanced CT (NECT) and contrast-enhanced CT (CECT). Radiomics score (rad-score) of two CT scans was calculated respectively. A nomogram combining two CT scans was developed to evaluate T790M resistance within up to 14 months. Patients were followed up to calculate the time of T790M occurrence. Models were evaluated by area under the curve at receiver operating characteristic analysis (ROC-AUC), calibration curve, and decision curve analysis (DCA). The association of the nomogram with the time of T790M occurrence was evaluated by Kaplan–Meier survival analysis. Results: The nomogram constructed with the rad-score of NECT and CECT for predicting T790M resistance within 14 months achieved the highest ROC-AUCs of 0.828 and 0.853 in training and testing cohorts, respectively. The DCA showed that the nomogram was clinically useful. The Kaplan–Meier analysis showed that the occurrence time of T790M difference between the high- and low-risk groups distinguished by the rad-score was significant (p < 0.001). Conclusions: The CT-based radiomics signature may provide prognostic information and improve pretreatment risk stratification in EGFR NSCLC patients before EGFR-TKIs therapy. The multimodal radiomics nomogram further improved the capability. Relevance statement: Radiomics based on NECT and CECT images can effectively identify and stratify the risk of T790M resistance before the first-line TKIs treatment in metastatic non-small cell lung cancer patients. Key points: • Early identification of the risk of T790M resistance before TKIs treatment is clinically relevant. • Multimodel radiomics nomogram holds potential to be a diagnostic tool. • It provided an imaging surrogate for identifying the pretreatment risk of T790M. [ABSTRACT FROM AUTHOR]

Purpose Epidermal growth factor receptor (EGFR) T790M mutations have been detected in the second or third rebiopsy, even if the T790M mutation was not identified in the first rebiopsy. This meta-analysis investigated the EGFR T790M mutation detection rates and its additional advantages with repeated rebiopsies. Materials and Methods We searched through the PubMed and EMBASE databases up to June 2022. Studies reporting rebiopsy to identify the EGFR T790M mutation in case of disease progression among patients with advanced non-small cell lung cancer and multiple rebiopsies were included. The quality of the included studies was checked using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Results Eight studies meeting the eligibility criteria, reporting 1,031 EGFR mutation--positive patients were selected. The pooled EGFR T790M mutation detection rate of the first and repeated rebiopsies were 0.442 (95% confidence interval [CI], 0.411 to 0.473; I2=84%; p < 0.01) and 0.465 (95% CI, 0.400 to 0.530; I2=69%; p < 0.01), respectively. Overall, the pooled detection rate of EGFR T790M mutation was 0.545 (95% CI, 0.513 to 0.576), which increased by 10.3% with repeated rebiopsies. Conclusion This meta-analysis identified that repeated rebiopsy increases the detection rate of EGFR T790M mutation by 10.3%, even if EGFR T790M mutation is not detected in the first rebiopsy. Our results indicate that the spatiotemporal T790M heterogeneity can be overcome with repeated rebiopsy. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advancedstage epidermal growth factor receptor (EGFR)+ non--small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). Materials and Methods In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. Results The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5). Conclusion This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+. [ABSTRACT FROM AUTHOR]

Purpose In patients with epidermal growth factor receptor (EGFR)-mutant non--small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs. Materials and Methods We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI--resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed. Results High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI. Conclusion High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI--resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI--resistant patients with EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations. Methods: This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Results: Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6–17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5–34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5–18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs). Conclusions: Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations. Trial registration: ClinicalTrials.gov identifier: NCT03736837. [ABSTRACT FROM AUTHOR]

Owing to the high rates of relapse and migration, ovarian cancer (OC) has been recognized as the most lethal gynecological malignancy worldwide. The activity of the epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with OC cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in OC patients failed to achieve satisfactory therapeutic effects. In this study, we identified that bruceine D (BD) and EGFR inhibitor, afatinib, combination resulted in synergistic anti-OC effects. The results indicated that compared with one of both drugs alone, the combination of BD and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of BD and afatinib possessed a stronger ability to inhibit the OC cell adhesion and migration than treatment with BD or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against OC treatment. The results support the potential of BD and afatinib combination as a therapeutic strategy for OC patients. [ABSTRACT FROM AUTHOR]

Purpose Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Materials and Methods Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. Results The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups. Conclusion Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC. [ABSTRACT FROM AUTHOR]

Overexpression and mutations of the epidermal growth factor receptor (EGFR/ErbB1/HER1) and other tyrosine kinase receptors of the ErbB family (ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) play an essential role in enhancing the proliferation, the migratory capacity and invasiveness of many tumor cells, leading to cancer progression and increased malignancy. To understand these cellular processes in detail is essential to understand at a molecular level the signaling pathways and regulatory mechanisms controlling these receptors. In this regard, calmodulin (CaM) is a Ca2+-sensor protein that directly interacts with and regulates ErbB receptors, as well as some CaM-dependent kinases that also regulate these receptors, particularly EGFR and ErbB2, adding an additional layer of CaM-dependent regulation to this system. In this short review, an update of recent advances in this area is presented, covering the direct action of Ca2+/CaM on the four ErbB family members mostly in tumor cells and the indirect action of Ca2+/CaM on the receptors via CaM-regulated kinases. It is expected that further understanding of the CaM-dependent mechanisms regulating the ErbB receptors in future studies could identify new therapeutic targets in these systems that could help to control or delay cancer progression. [ABSTRACT FROM AUTHOR]

The strong association between endometriosis and infertility is of high clinical significance. High proliferative bias in eutopic endometrium during the secretory phase is a hallmark of endometriosis, which may result in high occurrence of implantation failure and resultant infertility in endometriosis. The ErbB family of proteins regulates the proliferation capacity in the endometrium, potentially causing endometrial hostility to the implantation process in endometriosis. However, our knowledge regarding the involvement of the ErbB family in human endometrium during the window of implantation (WOI) in endometriosis-associated infertility is scant. In the present study, the cellular profiles of immunopositive ErbBs-1 to -4 in the endometrium of endometriosis-free, infertile women (Group 1; n = 11) and in eutopic endometrium of infertile women diagnosed with stage IV ovarian endometriosis (Group 2; n = 13) during the mid-secretory phase were compared using standardized guidelines. Computer-aided standardized combinative analysis of immunoprecipitation in different compartments revealed an overexpression of ErbB-1 in the epithelial, stromal and vascular compartments, along with marginally higher ErbB-3 expression (p < 0.06) in the vascular compartment and ErbB-4 expression (p < 0.05) in the glandular epithelium and stroma in the endometrium during the WOI in women with primary infertility associated with stage IV ovarian endometriosis compared with disease-free endometrium of control infertile women. It appears that changes in ErbBs in the eutopic endometrium during WOI induce anomalous proliferative, inflammatory and angiogenic activities in it, which can antagonize endometrial preparation for embryo implantation in endometriosis. This knowledge appears usable in strategizing methods for the treatment of endometriosis-associated infertility, as well as preempting the oncogenic potential of endometriosis. [ABSTRACT FROM AUTHOR]

The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti‐epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM‐TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two‐thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression‐free survival (PFS) of anti‐EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti‐EGFR antibody agents. [ABSTRACT FROM AUTHOR]

Background: Novel treatments of neuropathic pain are urgently needed. Rapid relief of neuropathic cancer pain in patients treated with epidermal growth factor receptor (EGFR) inhibitors have been reported. Experiments in rodent models confirm the pain relief and reveal novel mechanisms critically involving the EGFR. Clinical pain research is complicated and patients with advanced cancer are heterogeneous, often with complex, deteriorating clinical pictures, hampering feasibility of drug-trial procedures. Actual case: Prospective case series exploring the EGFR inhibition/neuropathic cancer pain association in order to inform planning clinical trials. Possible courses of action: Symptom assessment method was tailored to what was ethical, feasible, and clinically relevant for each patient. Formulation of a plan: Patients with neuropathic cancer pain treated off-label with the monoclonal antibody panitumumab were studied to assess feasibility of different measurement tools. Outcome: Fourteen of 20 patients (70%) experienced clinically significant pain relief. There was good concordance in patient and physician-reported outcomes. Lessons: Results support panitumumab's potential to be of significant benefit to patients with refractory neuropathic cancer pain. Findings also reinforce the difficulty of using conventional drug trial endpoints and designs in this population. View: Innovative research methods must be considered for much needed pivotal trials. [ABSTRACT FROM AUTHOR]

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor derivatives play an important role in the treatment of cancer. We aim to construct 2D-QSAR models using various chemometrics using 4-anilinoquinazoline-containing EGFR TKIs. In addition, the binding profile of these compounds was evaluated using a docking study. Materials and Methods: In this study, 122 compounds of seven different structural categories with a 4-anilinoquinazoline scaffold were obtained from the pieces of literature. 2D-QSAR models were prepared using the linear method, including multiple linear regression (MLR), alongside non-linear methods, including artificial neural networks (ANN) and support vector machines (SVM). The validation of suggested 2D-QSAR models was performed using internal and external validation techniques. For molecular docking, three compounds, including compounds 32, 75, and 98, which had the highest pIC50, were used. Molecular docking was performed using AutoDock 4.2. Results: Selected descriptors indicated that atomic electronegativity, hydrogen bonding ability, lipophilicity, and molecular shape and volume were the factors affecting the activity of the compounds. Statistical criteria, related to interpretation and validation of the models, were in the appropriate range. The model obtained by the ANN method, with the lowest mean absolute error of 0.365 for both training and testing sets, was the best. The compound 75 as the most potent compound indicated binding energies of -8.33 kcal/mol. Conclusion: Finally, it was found that the models could effectively predict the activity of the compounds. It was also discovered that the compounds were properly bound to the active site of the receptor. In addition, validation results showed that all processes were sufficiently valid. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients. Materials and Methods From August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis. Results A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFRTKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481). Conclusion Our research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

The glycosylation of cell surface receptors has been shown to regulate each step of signal transduction, including receptor trafficking to the cell surface, ligand binding, dimerization, phosphorylation, and endocytosis. In this review we focus on the role of glycosyltransferases that are involved in the modification of N-glycans, such as the effect of branching and elongation in signaling by various cell surface receptors. In addition, the role of those enzymes in the EMT/MET programs, as related to differentiation and cancer development, progress and therapy resistance is discussed. [ABSTRACT FROM AUTHOR]

Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with H2O2 alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with H2O2 combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after H2O2 treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed ErbB2 and OGG1 increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration via a different modulation of PI3K and MAPKs pathways. Moreover, the observed ErbB2 and OGG1 induction is a cellular response to protect the cells from H2O2-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated neuromuscular junctions and reduced glial reactivity in the spinal cord of the treated SOD1G93A mice. Moreover, NRG1 isoforms overexpression improved motor function of hindlimb muscles and delayed the onset of clinical disease. However, this combinatory gene therapy did not produce a synergic effect compared with single therapies, suggesting an overlap between NRG1-I and NRG1-III activated pathways and their beneficial effects. [ABSTRACT FROM AUTHOR]

Purpose The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digitaldroplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. Results CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients. [ABSTRACT FROM AUTHOR]

Background: Genetic interactions are known to play an important role in the missing heritability problem for type 2 diabetes mellitus (T2DM). Interactions between enhancers and their target genes play important roles in gene regulation and disease pathogenesis. In the present study, we aimed to identify genetic interactions between enhancers and their target genes associated with T2DM. Methods: We performed genetic interaction analyses of enhancers and protein-coding genes for T2DM in 2,696 T2DM patients and 3,548 controls of European ancestry. A linear regression model was used to identify single nucleotide polymorphism (SNP) pairs that could affect the expression of the protein-coding genes. Differential expression analyses were used to identify differentially expressed susceptibility genes in diabetic and nondiabetic subjects. Results: We identified one SNP pair, rs4947941×rs7785013, significantly associated with T2DM (combined P=4.84×10-10). The SNP rs4947941 was annotated as an enhancer, and rs7785013 was located in the epidermal growth factor receptor (EGFR) gene. This SNP pair was significantly associated with EGFR expression in the pancreas (P=0.033), and the minor allele "A" of rs7785013 decreased EGFR gene expression and the risk of T2DM with an increase in the dosage of "T" of rs4947941. EGFR expression was significantly upregulated in T2DM patients, which was consistent with the effect of rs4947941×rs7785013 on T2DM and EGFR expression. A functional validation study using the Mouse Genome Informatics (MGI) database showed that EGFR was associated with diabetes-relevant phenotypes. Conclusion: Genetic interaction analyses of enhancers and protein-coding genes suggested that EGFR may be a novel susceptibility gene for T2DM. [ABSTRACT FROM AUTHOR]

The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion. [ABSTRACT FROM AUTHOR]

Various external factors modulate the metabolic efficiency of mitochondria. This review focuses on the impact of the growth factor neuregulin and its ErbB receptors on mitochondria and their relationship with several physiopathological alterations. Neuregulin is involved in the differentiation of heart, skeletal muscle, and the neuronal system, among others; and its deficiency is deleterious for the health. Information gathered over the last two decades suggests that neuregulin plays a key role in regulating the mitochondrial oxidative machinery, which sustains cell survival and insulin sensitivity. [ABSTRACT FROM AUTHOR]

Neuregulin-1 (NR G-1) is a type of epidermal growth factor-like protein primarily distributed in the nervous and cardiovascular systems. When sepsis occurs, the incidence of cardiac dysfunction in myocardial injury is high and the mechanism is complicated. It directly causes myocardial cell damage, whilst also causing damage to the structure and function of myocardial cells, weakening of endothelial function and coronary microcirculation, autonomic dysfunction, and activation of myocardial inhibitory factors. Studies investigating NR G-1 have been performed using a variety of methods, including in vitro models, and animal and human clinical trials; however, the results are not consistent. NR G-1/ErbBs signaling is involved in a variety of cardiac processes, from the development of the myocardium and cardiac conduction systems to the promotion of angiogenesis in cardiomyocytes, and in cardio-protective effects during injury. NR G-1 may exert a multifaceted cardiovascular protective effect by activating NR G-1/ErbBs signaling and regulating multiple downstream signaling pathways, thereby improving myocardial cell dysfunction in sepsis, and protecting cardiomyocytes and endothelial cells. It may alleviate myocardial microvascular endothelial injury in sepsis; its anti-inflammatory effects inhibit the production of myocardial inhibitory factors in sepsis, improve myocardial ischemia, decrease oxidative stress, regulate the disruption to the homeostasis of the autonomic nervous system, improve diastolic function, and offer protective effects at multiple target sites. As the mechanism of action of NR G-1 intersects with the pathways involved in the pathogenesis of sepsis, it may be applicable as a treatment strategy to numerous pathological processes in sepsis. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy among females worldwide. Recent studies have shown extra-ribosomal roles of the moonlight ribosomal proteins in the development of human cancers. Accurate quantification of the gene expression level is based on the selection of the reference genes whose expression is independent of cancer properties and patient's characteristics. The aim of this study was the evaluation of the expression level of a previously proposed ribosomal protein as moonlight, L13a (RPL13A), in breast cancer samples and their adjacent tissues. Its association with genes of known roles in developing cancers was also investigated. Traditionally used housekeeping genes were selected and their expression was analyzed in 80 surgically excised breast tissue specimens (40 tumors and 40 tumor-adjacent tissues) by applying three software tools including GeNorm, NormFinder, and BestKeeper to select the most stable reference genes. Then, mRNA expression levels of RPL13A and p53 were evaluated. Additionally, protein expression levels of RPL13A were measured. It was demonstrated that PUM1 and ACTB are the most reliable reference genes and RPL13A is the least stable gene. There was a positive correlation between RPL13A and p53 mRNA expression levels in all the tumor samples. Moreover, significant downregulation of RPL13A expression levels was revealed in HER2+ tumor samples compared to HER2- ones. There was also a marked decrease in p53 mRNA expression levels in HER2+ tumor subtypes. Our results suggest that there is a probable relationship between RPL13A decreased expression with p53 and HER2/neu expression in the breast cancer. [ABSTRACT FROM AUTHOR]

Background: Afatinib is an irreversible ErbB family blocker that improves progression‐free survival (PFS) of advanced EGFR‐mutant lung adenocarcinoma compared to chemotherapy. However, afatinib leads to more adverse events than first‐generation EGFR inhibitors. Hence, exploration of the optimal afatinib initial dose and its efficacy and safety in Asian patients has drawn extensive attention. Methods: We retrospectively evaluated demographic and clinical information, survival data, and adverse events in advanced non‐small cell lung cancer patients treated with afatinib from 27 February 2017 to 30 October 2018. Results: A total of 60 patients were included in the study. Thirty‐nine (65%) patients received afatinib as first‐line treatment. The median PFS was 12.3 months (95% confidence internal 7.6–17.0). Multivariate Cox regression analysis revealed that age, gender, smoking history, baseline brain metastasis status, afatinib starting dose, and mutation type did not significantly influence PFS. No significant difference in median PFS between patients treated with an initial dose of afatinib of 40 mg or 30 mg, either in the first‐line (14.5 vs. 5.2 months; P = 0.101) or in a second or later‐line setting (3.0 vs. 5.0 months; P = 0.375) was observed. The incidence of all grades of rash/acne (92.5% vs. 61.1%; P = 0.011) and paronychia (82.5% vs. 50.0%; P = 0.010) in the 40 mg group was significantly higher than in the 30 mg group. Conclusion: First‐line afatinib treatment is beneficial for advanced lung adenocarcinoma patients with sensitive EGFR mutations. Initial dose and baseline brain metastasis status do not significantly impact PFS. [ABSTRACT FROM AUTHOR]

The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines. [ABSTRACT FROM AUTHOR]

Neuregulin‑1 (NRG‑1) is a positive regulator of angiogenesis, which suggests there may be an association between NRG‑1 and angiogenic factors. The aim of the present study was to investigate the effect of treating human cardiac microvascular endothelial cells (HCMECs) with angiogenic factors on NRG‑1 expression and secretion. HCMECs were cultured and stimulated with vascular endothelial growth factor (VEGF; 100 ng/ml), angiopoietin (Ang)‑1 (100 ng/ml) or Ang‑2 (100 ng/ml) under normal or hypoxia/serum deprivation (Hypo/SD) conditions for 24 h. The expression of ErbB receptors and NRG‑1 in HCMECs was measured by western blot analysis and the secretion of NRG‑1 in HCMECs was determined by ELISA. The results demonstrated that ErbB2, ErbB3 and ErbB4 were expressed in HCMECs and that ErbB2 expression levels were notably higher than those of ErbB3 and ErbB4. Under normal culture conditions the expression and secretion of NRG‑1 was significantly increased in HCMECs treated with VEGF or Ang‑1 (P<0.05), however levels significantly decreased in HCMECs treated with Ang‑2 (P<0.05). Under Hypo/SD conditions the expression and secretion of NRG‑1 significantly increased (P<0.05) and VEGF or Ang‑1 treatment significantly increased these effects further (P<0.05). Conversely Ang‑2 treatment significantly decreased these effects (P<0.05). The expression and release of NRG‑1 were significantly increased in HCMECs with VEGF or Ang‑1 treatment (P<0.05), which suggests that VEGF and Ang‑1 may regulate myocardial angiogenesis and survival via the NRG‑1/ErbB signaling pathway. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with no effective treatment currently available. Although the mechanisms of motoneuron (MN) death are still unclear, glutamate excitotoxicity and neuroinflammatory reaction are two main features in the neurodegenerative process of ALS. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Several recent evidences suggest that NRG1 and their ErbB receptors are involved in ALS. However, further knowledge is still needed to clarify the role of the NRG1-ErbB pathway on MN survival. In this study we used an in vitro model of spinal cord organotypic cultures (SCOCs) subject to chronic excitotoxicity caused by DL-threo-β-hydroxyaspartic acid (THA) to characterize the effect of NRG1 on MN survival. Our results show that addition of recombinant human NRG1 (rhNRG1) to the medium significantly increased MN survival through the activation of ErbB receptors which was ablated with lapatinib (LP), an ErbB inhibitor, and reduced microglial reactivity overcoming the excitotoxicity effects. rhNRG1 activated the pro-survival PI3K/AKT pathway and restored the autophagic flux in the spinal cord culture. Moreover, addition of rhNRG1 to the medium promoted motor and sensory neurite outgrowth. These findings indicate that increasing NRG1 at the spinal cord is an interesting approach for promoting MN protection and regeneration. [ABSTRACT FROM AUTHOR]

The second member of the human ErbB family of receptor tyrosine kinases, HER2/hErbB2, is regarded as an exceptional case: The four extracellular subdomains could so far only be found in one fixed overall conformation, designated “open” and resembling the ligand-bound form of the other ErbB receptors. It thus appears to be different from the extracellular domains of the other family members that show inter-subdomain flexibility and exist in a “tethered” form in the absence of ligand. For HER2, there was so far no direct evidence for such a tethered conformation on the cell surface. Nonetheless, alternative conformations of HER2 in vivo could so far not be excluded. We now demonstrate the rigidity of HER2 on the surface of tumor cells by employing two orthogonal approaches of protein engineering: To directly test the potential of the extracellular domain of HER2 to adopt a pseudo-tethered conformation on the cell surface, we first designed HER2 variants with a destabilized interface between extracellular subdomains I and III that would favor deviation from the “open” conformation. Secondly, we used differently shaped versions of a Designed Ankyrin Repeat Protein (DARPin) fusion, recognizing subdomain I of HER2, devised to work as probes for a putative pseudo-tethered extracellular domain of HER2. Combining our approaches, we exclude, on live cells and in vitro, that significant proportions of HER2 deviate from the “open” conformation. [ABSTRACT FROM AUTHOR]

Hormone therapy has become one of the main strategies for breast cancer, however, many estrogen receptor ( ER) positive patients end in tumor collapse due to initial or acquired resistance to hormone treatment, which includes Fulvestrant. Here we report that ErbB receptors and downstream PI3K/ AKT and ERK pathway have been reactivated after treatment of Fulvestrant in ER positive MCF-7 and T47D cells, which are related to Fulvestrant resistance. HSP90 is a universally expressed chaperone protein and plays a vital role in both normal and cancer cells, HSP90 inhibitor AUY922 can reverse this feedback reactivation effect of Fulvestrant by targeting multiple proteins related in ErbB receptors, PI3K/ AKT and ERK pathway, which is much better than single targeting inhibitors. We also consolidate these effects in human fresh breast tumors. Combination of AUY922 and Fulvestrant may become a promising therapy strategy in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient’s cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity. To realize the promise of ‘personalized medicine’, it will be important to develop a more integrated understanding of the relationships between oncogenic events and processes governing anti-tumor immunity. One area of investigation to explore such relationships centers on defining how ErbB/HER activation and signal transduction influences antigen processing and presentation. [ABSTRACT FROM AUTHOR]

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Growth factors mediate their diverse biologic responses (regulation of cellular proliferation, differentiation, migration and survival) by binding to and activating cellsurface receptors with intrinsic protein kinase activity named receptor tyrosine kinases (RTKs). About 60 RTKs have been identified and can be classified into more than 16 different receptor families. Their activity is normally tightly controlled and regulated. Overexpression of RTK proteins or functional alterations caused by mutations in the corresponding genes or abnormal stimulation by autocrine growth factor loops contribute to constitutive RTK signaling, resulting in alterations in the physiological activities of cells. The ErbB receptor family of RTKs comprises four distinct receptors: the EGFR (also known as ErbB1/HER1), ErbB2 (neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). ErbB family members are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. EGFR has been found to be amplified in gliomas and non-small-cell lung carcinoma while ErbB2 amplifications are seen in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. Several data have shown that ErbB receptor family and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion by modulating extracellular matrix (ECM) components. Recent findings indicate that ECM components such as matrikines bind specifically to EGF receptor and promote cell invasion. In this review, we will present an in-depth overview of the structure, mechanisms, cell signaling, and functions of ErbB family receptors in cell adhesion and migration. Furthermore, we will describe in a last part the new strategies developed in anti-cancer therapy to inhibit ErbB family receptor activation. [ABSTRACT FROM AUTHOR]

Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naï ve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported. Results. In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected. Conclusion. Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naTve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations. [ABSTRACT FROM AUTHOR]

Neuregulin-1 (NRG-1) and its signaling receptors, erythroblastic leukemia viral oncogene homologs (ErbB) 2, 3, and 4, have been implicated in both cardiomyocyte development and disease, as well as in homeostatic cardiac function. NRG-1/ErbB signaling is involved in a multitude of cardiac processes ranging from myocardial and cardiac conduction system development to angiogenic support of cardiomyocytes, to cardioprotective effects upon injury. Numerous studies of NRG-1 employ a variety of platforms, including in vitro assays, animal models, and human clinical trials, with equally varying and, sometimes, contradictory outcomes. NRG-1 has the potential to be used as a therapeutic tool in stem cell therapies, tissue engineering applications, and clinical diagnostics and treatment. This review presents a concise summary of the growing body of literature to highlight the temporally persistent significance of NRG-1/ErbB signaling throughout development, homeostasis, and disease in the heart, specifically in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed. [ABSTRACT FROM AUTHOR]

ErbB receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ErbB inhibitors are now used in the clinical setting. A large number of studies have been conducted to examine the expression of ErbB family members in bone and soft tissue sarcomas, including osteosarcomas, synovial sarcomas, Ewing sarcomas, rhabdomyosarcomas, and so on. Nevertheless, the clinical implications of ErbB receptors remain elusive. To illustrate the potential of ErbB family members as prognostic and therapeutic drug targets in bone and soft tissue sarcomas, we summarized the molecular evidence and observations from clinical and basic trials. [ABSTRACT FROM AUTHOR]

C boutons are large, cholinergic, synaptic terminals that arise from local intemeurons and specifically contact spinal α-motoneurons (MNs). C boutons characteristically display a postsynaptic specialization consisting of an endoplasmic reticulum-related subsurface cistern (SSC) of unknown function. In the present work, by using confocal microscopy and ultrastructural immunolabeling, we demonstrate that neuregulin-1 (NRG1) accumulates in the SSC of mouse spinal MNs. We also show that the NRG1 receptors erbB2 and erbB4 are presynaptically localized within C boutons, suggesting that NRGl-based retrograde signaling may occur in this type of synapse. In most of the cranial nuclei, MNs display the same pattern of NRG1 distribution as that observed in spinal cord MNs. Conversely, MNs in oculomotor nuclei, which are spared in amyotrophic lateral sclerosis (ALS), lack both C boutons and SSC-associated NRG1. NRG1 in spinal MNs is developmentally regulated and depends on the maintenance of nerve-muscle interactions, as we show after nerve transection experiments. Changes in NRG1 in C boutons were also investigated in mouse models of MN diseases: i.e., spinal muscular atrophy (SMNΔ 7) and ALS (SOD1G93A). In both models, a transient increase in NRG1 in C boutons occurs during disease progression. These data increase our understanding of the role of C boutons in MN physiology and pathology. [ABSTRACT FROM AUTHOR]

The National Cancer Institute estimates that approximately 13.7 million Americans with a history of cancer were alive on January 1, 2012. With the rising number of cancer survivors, there is an increased focus on how chemotherapy agents modulate the cardiovascular biology and cause chemotherapy-related heart failure in certain patients. Neuregulin-1 (NRG-1) is an important cardiac growth factor that is essential for normal myocardial development and maintenance. Certain chemotherapy agents perturb the normal NRG-1 signaling in the cardiovascular system and cause cardiac dysfunction and, in some cases, symptomatic heart failure. As researchers have learned the critical importance of NRG-1 within the cardiovascular system, more attention has been focused on the potential use of NRG-1 as biomarker and therapy for the treatment of heart failure. This review will highlight the biology of NRG-1 within the cardiovascular system, its role in chemotherapy-induced heart failure, and the translational potential of NRG-1 as treatment for heart failure. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumors (MPNSTs) are Schwann cell-derived malignancies that arise from plexiform neurofibromas in patients with mutation of the neurofibromin 1 ( NF1) gene. We have shown that the growth factor neuregulin-1 (NRG1) also contributes to human neurofibroma and MPNST pathogenesis and that outbred C57BL/6J × SJL/J transgenic mice overexpressing NRG1 in Schwann cells (P-GGFβ3 mice) recapitulate the process of neurofibroma-MPNST progression. However, it is unclear whether NRG1 acts predominantly within NF1-regulated signaling cascades or instead activates other essential cascades that cooperate with NF1 loss to promote tumorigenesis. We now report that tumorigenesis is suppressed in inbred P-GGFβ3 mice on a C57BL/6J background. To determine whether NRG1 overexpression interacts with reduced Nf1 or Trp53 gene dosage to 'unmask' tumorigenesis in these animals, we followed cohorts of inbred P-GGFβ3; Nf1, P-GGFβ3; Trp53 and control (P-GGFβ3, Nf1 and Trp53) mice for 1 year. We found no reduction in survival or tumors in control and P-GGFβ3 ;Nf1 mice. In contrast, P-GGFβ3; Trp53 mice died on average at 226 days, with MPNSTs present in 95 % of these mice. MPNSTs in inbred P-GGFβ3; Trp53 mice arose de novo from micro-MPNSTs that uniformly develop intraganglionically. These micro-MPNSTs are of lower grade (WHO grade II-III) than the major MPNSTs (WHO grade III-IV); array comparative genomic hybridization showed that lower grade MPNSTs also had fewer genomic abnormalities. Thus, P-GGFβ3; Trp53 mice represent a novel model of low- to high-grade MPNST progression. We further conclude that NRG1 promotes peripheral nervous system neoplasia predominantly via its effects on the signaling cascades affected by Nf1 loss. [ABSTRACT FROM AUTHOR]

ErbB receptors not only function in cancer, but are also key developmental regulators in the nervous system. We previously identified an ErbB1 peptide antagonist, Inherbin3, that is capable of inhibiting tumor growth in vitro and in vivo. In this study, we found that inhibition of ErbB1 kinase activity and activation of ErbB4 by NRG-1β induced neurite extension, suggesting that ErbB1 and ErbB4 act as negative and positive regulators, respectively, of the neuritogenic response. Inherbin3, inhibited activation not only of ErbB1 but also of ErbB4 in primary neurons, strongly induced neurite outgrowth in rat cerebellar granule neurons, indicating that this effect mainly was due to inhibition of ErbB1 activation. [ABSTRACT FROM AUTHOR]

Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyperactivation of mitogen-activated protein kinase (MAPK) and PI3K/Akt, which mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationships between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K/Akt and MAPK/ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a human non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the results obtained by gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/PTC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells). Gene expression data also delineated that MUTYH gene could play a physiological role in crosstalk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall, our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements. [ABSTRACT FROM AUTHOR]

Ligand-mediated activation of ErbB3 and ErbB4 is implicated in the pathogenesis of several human malignancies including cancer of the ovary and melanoma. We have used the broad ErbB ligand specificity of ErbB4 to assemble and express an ErbB4 fusion protein comprising the first 497 amino acids of the mature ErbB4 ectodomain fused to the human IgG Fc constant region. The purified fusion protein, designated sErbB4.497.Fc, binds the ErbB receptor ligands betacellulin and heregulin-β1 (HRG-β1) with high affinity ( KD = 130 pM), an increase in affinity of 10- to 20-fold, respectively, compared with sErbB4.615.Fc. sErbB4.497.Fc inhibited ligand-stimulated phosphorylation of epidermal growth factor receptor and ErbB2, and blocked HRG-β1 activation of the IKB/MAP/JNK/AKT signalling pathways. sErbB4.497.Fc inhibited HRG-β1-stimulated proliferation in MCF7 cells. In a mouse tumour xenograft model, sErbB4.497.Fc as a monotherapy modestly inhibited the growth of MDA-MB-231 breast cancer cells. sErbB4.497.Fc may be useful in an adjuvant setting in combination with conventional therapeutic agents. [ABSTRACT FROM AUTHOR]