Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors

描述（由申请人提供）：整合素αvβ3在大多数侵袭性和转移性癌症中表达。在这里，新的实验数据表明αvβ3也驱动了对egfr靶向治疗的新抗性途径。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后，存活细胞亚群中整合素β3亚基的表达增强。机制上，αvβ3整合素促进致癌K-Ras的质膜聚集，驱动其向RalB及其下游效应物的信号传导。这个αvβ3/K-Ras/RalB“致癌单位”不仅增加体外锚定依赖性和体内肿瘤生长，而且使肿瘤对EGFR抑制具有抗性。这些发现表明，这种新途径的失能成分可能会增强对egfr靶向治疗的敏感性。本提案中概述的实验将在体外和体内研究αvβ3/K-Ras相互作用在许多上皮癌的EGFR抑制剂耐药性方面的意义。Aim 1的目的是确定整合素αvβ3和K-Ras之间关联的结构基础，K-Ras似乎在上皮癌细胞中驱动RalB介导的信号传导。Aim 2的研究旨在确定哪些β3/K- Ras/RalB效应物驱动锚定依赖性和厄洛替尼耐药性，并在体外测试阻断该途径的遗传和药理学策略。最后，Aim 3将评估克服皮下和原位小鼠肿瘤模型中EGFR抑制剂耐药性的策略。如果成功，这些研究将支持临床继续使用egfr靶向治疗，并提供新的策略来改善肿瘤获得耐药性后对此类治疗的反应。

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.