FGF2 Signaling as a Clinically Relevant Resistance Mechanism to TKIs in GIST

描述（由申请人提供）：胃肠道间质瘤是胃肠道最常见的间叶肿瘤。 转移性或不可手术的GIST的当前护理标准，靶向受体酪氨酸激酶KIT的小分子抑制剂治疗，极大地改善了患有这种疾病的患者的结局。然而，许多最初对治疗有反应的患者在几年内表现出难治性疾病。在这些情况下，选择仍然是 有限，患者面临更严重副作用的治疗选择。GIST也是实体瘤靶向治疗的范例，这种疾病的发现可以很好地外推到其他类型的癌症。 本申请中描述的项目的目的是研究成纤维细胞生长因子2（FGF 2）如何促进胃肠道间质瘤（GIST）中伊马替尼耐药的发展。在该目标下，从初步数据中提取的目的将是1）使用双分子荧光互补（BiFC）显微镜表征受体酪氨酸激酶KIT和成纤维细胞生长因子受体3之间的潜在直接相互作用，2）确定新型伊马替尼抗性GIST细胞系中FGF 2上调的机制，并评价该机制在GIST患者样品中的临床相关性，和3）确定在GIST中肿瘤内源性FGF 2表达和对靶向治疗的抗性之间是否存在统计学上显著的相关性和功能联系。本论文的研究将有助于对GIST细胞信号转导和抗性机制的理解。这些发现有可能为GIST患者的分层提供新的标志物，和/或使用新的靶向治疗或联合治疗的理由，最终目的是预测或克服这种疾病对靶向治疗的耐药性。因此，该项目解决了GIST领域最紧迫的问题，这对患者的生活质量和总体生存率有很大的影响。

DESCRIPTION (provided by applicant): Gastrointestinal Stromal Tumor is the most common mesenchymal tumor of the GI tract. The current standard of care for metastatic or inoperable GIST, therapy with small molecule inhibitors targeting the receptor tyrosine kinase KIT, has vastly improved the outcome for patients with this disease. However, many patients who initially respond to therapy exhibit refractory disease within a few years. In these cases, options are still limited, and patients face therapy choices with more severe side effects. GIST is also a paradigm for targeted treatment in solid tumors, and findings in this disease may well be extrapolated to other types of cancer. The goal of the project described in this application is t investigate how Fibroblast Growth Factor 2 (FGF2) contributes to the development of imatinib resistance in Gatrointestinal Stromal Tumor (GIST). Under this goal, aims drawing from preliminary data will be to 1) Characterize a potential direct interaction between the receptor tyrosine kinases KIT and Fibroblast Growth Factor Receptor 3 using Bimolecular Fluorescence Complementation (BiFC) microscopy, 2) Determine the mechanism of FGF2 upregulation in a novel imatinib-resistant GIST cell line, and evaluate the clinical relevance of this mechanism in GIST patient samples, and 3) Determine whether there is a statistically significant correlation and a functional link between tumor-intrinsic expression of FGF2 and resistance to targeted therapy in GIST. The thesis research will contribute to the mechanistic understanding of GIST cell signaling and resistance. Findings have the potential to provide new markers for the stratification of GIST patients, and/or rationale for the use of new targeted therapeutics or combination therapies, with the ultimate aim of anticipating or overcoming resistance to targeted therapy in this disease. Thus, this project addresses the most pressing question in the GIST field, which has a large impact on patients' quality of life and overall survival.