Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors

描述(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。在这里，新的实验数据表明，？V？3也驱动了对EGFR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？3亚单位的表达增强。在机制上，？V？3整合素促进致癌K-RAS的质膜聚集，从而驱动其向RalB及其下游效应分子传递信号。这种？V？3/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EGFR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。这项建议中概述的实验将检验？V？3/K-RAS相互作用在体内和体外对一些上皮性肿瘤的EGFR抑制剂耐药的意义。目标1的目的是确定整合素？V？3和K-RAS之间的联系的结构基础，这似乎驱动RalB介导的上皮性癌细胞信号转导。AIM 2的研究旨在确定哪种？3/K-RAS/RalB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 ?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.