P1 - Molecular Mechanisms of KIT Signaling and Imatinib Resistance in GIST

胃肠道间质瘤(GIST)是由KIT受体酪氨酸激酶驱动的，大多数具有获得性功能。 KIT或偶尔在PDGFRA中发生突变。伊马替尼抑制KIT和PDGFRA，产生 80%的GIST患者部分缓解或病情稳定，但完全缓解的情况很少见。此外，关于 从伊马替尼治疗中受益的患者中，有一半最终出现抗药性，其他患者很少 治疗方法是可用的。获得性耐药的一个常见机制是第二位点Kit突变。 我们提出了4个总体目标。(1)使用基因组方法确定替代信号 GIST缺乏KIT或PDGFRA突变和伊马替尼耐药GIST缺乏可识别的 抗性机制。候选基因将被验证，并应用通径分析来识别 潜在的治疗目标。(2)鉴定对伊马替尼或其他激酶产生抗药性的突变 抑制剂，以制定针对不同基因的治疗指南。(3)研究新型药理作用 伊马替尼反应性GIST模型KitV558del/+小鼠体内干预策略(四)发展 建立伊马替尼耐药小鼠模型，并将其应用于评估伊马替尼耐药的新治疗策略 基特。接受测试的治疗策略是单独使用第二代酪氨酸激酶抑制剂。 并与KIT下游效应物的抑制物结合，靶向PI 3-激酶、整合素和STAT 发信号。通过阐明在对伊马替尼耐药的GIST中活跃的通路和临床前研究，我们 目的为伊马替尼耐药的胃肠道间质瘤患者寻找新的治疗方案。

Gastrointestinal stromal tumors (GISTs) are driven by KIT receptor tyrosine kinase, and most have gain-offunction mutations In KIT or occasionally in PDGFRA. Imatinib, which inhibits KIT and PDGFRA, produces a partial response or stable disease in 80% of GIST patients, but complete response is rare. Moreover, about half of the patients who benefit from imatinib treatment eventually develop drug resistance, and few other treatments are available. A common mechanism of acquired resistance is second-site KIT mutations. We propose 4 overall objectives. (1) Use genomic approaches to identify alternative signaling pathways in GIST lacking KIT or PDGFRA mutations and in imatinib-resistant GIST lacking an Identifiable mechanism of resistance. Candidate genes will be validated and pathway analysis applied to identify potential targets for therapy. (2) Identify mutations that confer resistance to imatinib or to other kinase inhibitors so as to develop guidelines for genotype-tailored therapy. (3) Investigate novel pharmacological intervention strategies in vivo in the KitV558del/+ mouse, a model of imatinib-responsive GIST. (4) Develop imatinib-resistant mouse models and apply them for the evaluation of new treatment strategies for imatinibresistant GIST. The treatment strategies to be tested are second^generation tyrosine kinase inhibitors alone and In combination with inhibitors of downstream effectors of KIT, targeting PI 3-kinase, integrin, and STAT signaling. By elucidating the pathways active in imatinib-resistant GIST and by preclinical investigations, we aim to find new therapeutic options for patients with Imatinib-resistant GIST.