Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors

描述(申请人提供)：整合素αvβ3在最具侵袭性和转移性的癌症中表达。在这里，新的实验数据表明，αvEGFR3也驱动了对β靶向治疗的一种新的耐药途径。事实上，不同的上皮癌细胞株暴露于表皮生长因子受体抑制剂厄洛替尼或拉帕替尼数周后，存活细胞亚群中整合素β3亚单位的表达增强。从机制上讲，αvβ3整合素促进致癌K-RAS的质膜聚集，从而驱动其信号传导至RalB及其下游效应分子。这种αvβ3/K-RAS/RALB“致癌单位”不仅增加了体外的锚定独立性和体内的肿瘤生长，而且还使肿瘤对EGFR3/K-RAS/RAB的抑制产生了抵抗。这些发现表明，禁用这一新途径的组件可能会增强对EGFR靶向治疗的敏感性。这项提案中概述的实验将检验αvEGFR3/K-RAS相互作用在体外和体内对一些上皮性癌症的β抑制剂耐药性方面的意义。目标1的目的是确定整合素αv RAS 3和K-RAS之间联系的结构基础，K-RAS似乎驱动βB介导的上皮癌细胞信号转导。AIM 2的研究旨在确定哪些β3/K-RAS/RAB效应器驱动锚定非依赖性和厄洛替尼耐药，并在体外测试阻断这一途径的遗传和药物策略。最后，Aim 3将评估克服皮下和原位小鼠癌症模型中EGFR抑制剂耐药性的策略。如果成功，这些研究将支持EGFR靶向治疗在临床上的继续使用，并提供新的策略，一旦肿瘤获得耐药性，就可以改善对此类治疗的反应。

DESCRIPTION (provided by applicant): Integrin αvβ3 is expressed in the most aggressive and metastatic cancers. Here, new experimental data suggests that αvβ3 also drives a novel pathway of resistance to EGFR-targeted therapies. In fact, different epithelial carcinoma cell lines exposed to the EGFR inhibitors erlotinib or lapatinib for several weeks show enhanced expression of the integrin β3 subunit in the subpopulation of surviving cells. Mechanistically, αvβ3 integrin promotes the plasma membrane clustering of oncogenic K-Ras to drive its signaling to RalB and its downstream effectors. This αvβ3/K-Ras/RalB "oncogenic unit" not only increases anchorage-independence in vitro and tumor growth in vivo, but it also renders tumors resistant to EGFR inhibition. These findings suggest that disabling components of this novel pathway may enhance the sensitivity to EGFR-targeted therapies. Experiments outlined in this proposal will examine the significance of the αvβ3 /K-Ras interaction in terms of EGFR inhibitor resistance for a number of epithelial cancers in vitro and in vivo. The goal of Aim 1 is o define the structural basis for the association between integrin αvβ3 and K-Ras, which appears to drive RalB- mediated signaling in epithelial carcinoma cells. Studies in Aim 2 are designed to determine which β3/K- Ras/RalB effectors drive anchorage-independence and erlotinib resistance, and to test both genetic and pharmacological strategies to block this pathway in vitro. Finally, Aim 3 will evaluate strategies to overcome EGFR inhibitor resistance for subcutaneous and orthotopic mouse cancer models. If successful, these studies will support the continued use of EGFR-targeted therapies in the clinic, and offer novel strategies to improve response to such therapies once tumors acquire resistance.