Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors

性状（由申请人提供）：整合素？v？3在最具侵袭性和转移性的癌症中表达。新的实验数据表明，？v？3还驱动了对EGFR靶向治疗的耐药性的新途径。事实上，不同的上皮癌细胞系暴露于EGFR抑制剂厄洛替尼或拉帕替尼数周显示整合素？3亚单位的存活细胞亚群。机械地，？v？3整合素促进致癌K-Ras的质膜聚集以驱动其向RalB及其下游效应物的信号传导。这个吗？v？3/K-Ras/RalB“致癌单元”不仅增加体外锚定独立性和体内肿瘤生长，而且使肿瘤对EGFR抑制具有抗性。这些发现表明，这种新途径的禁用组件可能会增强EGFR靶向治疗的敏感性。在这项建议中概述的实验将研究的意义？v？3/K-Ras相互作用在体外和体内的EGFR抑制剂耐药性方面的一些上皮癌。目的1的目标是o定义整合素之间关联的结构基础？v？3和K-Ras，其似乎驱动上皮癌细胞中RalB介导的信号传导。目标2中的研究旨在确定哪一个？3/K-Ras/RalB效应子驱动锚定非依赖性和厄洛替尼抗性，并测试在体外阻断该途径的遗传和药理学策略。最后，目标3将评估克服皮下和原位小鼠癌症模型的EGFR抑制剂耐药性的策略。如果成功，这些研究将支持EGFR靶向治疗在临床中的持续使用，并提供新的策略，以改善一旦肿瘤获得耐药性时对此类治疗的反应。

DESCRIPTION (provided by applicant): Integrin ?v?3 is expressed in the most aggressive and metastatic cancers. Here, new experimental data suggests that ?v?3 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 ?3 subunit in the subpopulation of surviving cells. Mechanistically, ?v?3 integrin promotes the plasma membrane clustering of oncogenic K-Ras to drive its signaling to RalB and its downstream effectors. This ?v?3/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 ?v?3/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 ?v?3 and K-Ras, which appears to drive RalB- mediated signaling in epithelial carcinoma cells. Studies in Aim 2 are designed to determine which ?3/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.