Understanding the consequences of oncogenic mutations on FGFR signaling

了解致癌突变对 FGFR 信号传导的影响

• 批准号: 9326732
• 负责人: Molly Ryan
• 金额: $ 4.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326732
• 关键词: Adenoid Cystic Carcinoma; Automobile Driving; Biological Assay; Cancer Patient; Cell Line; Cell Proliferation; Cells; Climacteric; Clinic; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Combined Modality Therapy; Cultured Cells; Cytometry; Data; Development; Drug resistance; Embryonic Development; Enzymes; Epithelial; FDA approved; FGFR1 gene; FGFR2 gene; Fibroblast Growth Factor Receptors; Flow Cytometry; Future Generations; Gatekeeping; Generations; Gland; Growth; Head and Neck Cancer; Hematopoiesis; Immunofluorescence Immunologic; Knowledge; Laboratories; Lead; Malignant Neoplasms; Mesenchymal; Modification; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Operative Surgical Procedures; Patients; Phosphotransferases; Play; Population; Primary Neoplasm; Process; Proteins; Rare Diseases; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Reporting; Research; Resistance; Resolution; Role; Salivary Glands; Signal Transduction; Squamous Cell Lung Carcinoma; Stem cells; Techniques; Technology; Time; Tumor-Derived; Universities; Validation; Wound Healing; Xenograft procedure; angiogenesis; base; cancer stem cell; cancer therapy; cancer type; chemotherapy; epithelial to mesenchymal transition; experimental study; fibroblast growth factor 6; head and neck cancer patient; inhibitor/antagonist; insight; interest; metaplastic cell transformation; molecular targeted therapies; mutant; mutational status; overexpression; receptor expression; resistance mechanism; resistance mutation; response; small molecule; small molecule inhibitor; stemness; targeted treatment; tissue repair; treatment strategy; tumor; tumor growth; tumor progression; tumorigenesis

Project Summary/Abstract Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases (RTKs) normally involved in tissue repair, hematopoiesis, angiogenesis, and embryonic development; however, upon amplification and/or mutation they have been implicated in a number of cancer types, including non-small cell lung cancer (NSCLC) and more recently in adenoid cystic carcinoma (ACC). Small-molecule inhibitors of FGFRs have been developed and are in clinical trials for the treatment of NSCLC. Oncogenic mutations of FGFRs occur both independently of and in response to targeted inhibition. Drug resistance mutations are a devastating challenge with any targeted therapy, making it absolutely critical to have an understanding of resistance mechanisms before such inhibitors reach the clinic. A prevalent drug resistant mutant of FGFR1 is the V561M mutation, termed the gatekeeper mutation. Our lab has reported a 38-fold increase in the catalytic rate of V561M FGFR1 relative to the wild-type enzyme, and has recently uncovered evidence that this mutation drives the epithelial to mesenchymal transition (EMT), an important process in tumor metastasis, through modification of the downstream signaling of FGFR1. Using immunoblots, CyTOF (cytometry time of flight), and other cell-based assays, I propose to investigate the differences in downstream signaling driving the enhanced EMT observed in V561M FGFR1 relative to WT. The mechanistic insight I will gain regarding the gatekeeper mutation and its effects on EMT and signaling has critical implications for the development of future generations of inhibitors and in the use of combination therapies to treat cancer patients. As FGFRs continue to emerge as drivers of cancer, it is crucial to examine their roles in other cancer types. The Yarbrough lab (Yale University) has recently identified the amplification and mutation of FGFRs as potential drivers of adenoid cystic carcinoma (ACC), a rare disease that is partially driven through the formation of cancer stem cells (CSC). In collaboration with the Yarbrough lab, I propose to validate FGFR as a target for ACC therapy and to interrogate the role of a mutant FGFR2 in driving growth and/or stemness of ACC cells cultured directly from patient derived xenografts. I will use a variety of cell-based assays including immunoblots and CyTOF. ACC currently has no targeted therapy options; the validation of FGFR as a driver of tumor growth and CSC proliferation will be a huge step forward for the entire field of head and neck cancer treatment.

项目总结/摘要 成纤维细胞生长因子受体（FGFRs）是受体酪氨酸激酶（RTK），通常参与 组织修复、造血、血管生成和胚胎发育;然而，在扩增和/或 它们与许多癌症类型有关，包括非小细胞肺癌（NSCLC） 以及最近在腺样囊性癌（ACC）中的应用。FGFR的小分子抑制剂已经被广泛应用。 已开发并正在进行治疗NSCLC的临床试验。FGFR的致癌突变发生在 独立于靶向抑制并响应于靶向抑制。耐药性突变是一个毁灭性的挑战 任何有针对性的治疗，这使得了解耐药机制至关重要， 在这种抑制剂到达临床之前。FGFR 1的一种普遍的耐药突变体是V561 M突变， 称为看门人突变。我们的实验室已经报道了V561 M FGFR 1的催化速率增加了38倍。 相对于野生型酶，最近发现的证据表明，这种突变驱动上皮细胞， 间充质转化（EMT）是肿瘤转移的一个重要过程， FGFR 1的下游信号传导。使用免疫印迹、CyTOF（细胞术飞行时间）和其他基于细胞的方法， 检测，我建议调查下游信号驱动增强EMT的差异 相对于WT，在V561 M FGFR 1中观察到。我将获得的关于看门人的机械洞察力 突变及其对EMT和信号传导的影响对未来的发展具有重要意义。 本发明涉及多代抑制剂和使用组合疗法治疗癌症患者。 随着FGFRs继续成为癌症的驱动因素，研究它们在其他癌症中的作用至关重要。 类型Yarbrough实验室（耶鲁大学）最近已经确定了FGFR的扩增和突变， 腺样囊性癌（ACC）的潜在驱动因素，ACC是一种罕见的疾病， 癌症干细胞（CSC）与Yarbrough实验室合作，我建议验证FGFR作为目标 用于ACC治疗，并询问突变型FGFR 2在驱动ACC生长和/或干性中的作用。 直接从患者来源的异种移植物培养ACC细胞。我会用各种基于细胞的分析 包括免疫印迹和CyTOF。ACC目前没有靶向治疗选择; FGFR作为 肿瘤生长和CSC增殖的驱动因素将是整个头颈部领域的一个巨大进步， 癌症治疗