Role of EphA2 RTK in tumor resistance to EGFR/HER2 inhibitors

项目总结/摘要 分子靶向治疗的研究进展 已经产生了有希望的新疗法。然而，实现这一目标的一个主要障碍 无病生存就是抗药性这项研究的长期目标是 探讨耐药机制和耐药肿瘤的靶点治疗。这 本申请将具体确定EphA 2受体酪氨酸激酶在内源性和内源性调节中的作用， 获得性耐EGFR/HER 2抑制剂。 EGFR和HER 2属于受体酪氨酸激酶（RTK）的ErbB家族， 对于肿瘤的发生和转移进展至关重要。几种治疗策略 已经开发了靶向EGFR和HER 2/ErbB 2的药物，包括激酶抑制剂， 易瑞沙（吉非替尼）和抗体如赫赛汀（曲妥珠单抗）。尽管最初的疗效， 在临床上经常观察到内在和获得性耐药性。我们发现， 对抗EGFR/HER 2治疗的抗性的机制是EphA 2的上调，EphA 2是EphA 2的成员， Eph家族RTK EphA 2与许多类型的癌症有关，包括NSCLC， 胶质母细胞瘤、黑素瘤、乳腺癌、结肠直肠癌、膀胱癌、前列腺癌和卵巢癌。 此外，EphA 2表达水平与肿瘤恶性程度和患者存活率相关。 我们最近报道了EphA 2缺陷损害肿瘤的发生和转移进展， 在过度表达ErbB 2癌基因的肿瘤中。生化分析显示EphA 2 与HER 2或EGFR形成复合物并促进MAPK和Rho GT3的活化。 此外，MMTV-Neu肿瘤对EphA 2的治疗性处理敏感，表明 EphA 2在HER 2/EGFR依赖性肿瘤进展中起重要作用。基于 根据这些数据，我们假设EphA 2受体的过表达赋予了内源性和/或 对抗HER 2/EGFR治疗获得性耐药。为了验证这一假设，具体目标1将 研究EphA 2在对EGFR/HER 2抑制剂的内在和获得性抗性中的作用， 使用新的抗EphA 2人单克隆抗体。具体目标2将决定 EphA 2在抗性肿瘤细胞中被激活的分子机制。在一起， 这些研究将对理解药物的作用机制有重大的进展。 对基于Her 2/Erb 2的疗法的抗性。该项目的成功将提供强有力的理由 用于治疗EGFR/HER 2耐药的抗EphA 2治疗剂的快速临床开发 肿瘤，这将大大有利于退伍军人群体。

Project Summary/Abstract Recent advances in the development and application of molecularly targeted therapies for cancer have generated promising new treatments. However, a major obstacle to achieving disease-free survival is drug resistance. The long-term objective of this research is to investigate the mechanisms of drug resistance and target resistant tumors for treatment. This application will specifically determine the role of EphA2 receptor tyrosine kinase in intrinsic and acquired resistant to EGFR/HER2 inhibitors. EGFR and HER2 belong to the ErbB family of receptor tyrosine kinases (RTKs) that are critical for tumor initiation and metastatic progression. Several therapeutic strategies for targeting EGFR and HER2/ErbB2 have been developed, including kinase inhibitors such as Iressa (Gefitinib), and antibodies such as herceptin (Trastuzumab). In spite of initial efficacy, intrinsic and acquired drug resistance is frequently observed in the clinic. We found that one of the mechanisms of resistance to anti-EGFR/HER2 therapy is upregulation of EphA2, a member of Eph family RTKs. EphA2 has been linked to many types of cancer, including NSCLC, gliobastoma, melanoma, breast, colorectal, bladder, prostate and ovarian carcinomas. Moreover, the level of EphA2 expression correlates with tumor malignancy and patient survival. We recently reported that EphA2-deficiency impairs tumor initiation and metastatic progression in tumors overexpressing the ErbB2 oncogene. Biochemical analyses revealed that EphA2 forms a complex with HER2 or EGFR and promotes activation of MAPK and Rho GTPase. Additionally, MMTV-Neu tumors are sensitive to therapeutic treatment of EphA2, suggesting that EphA2 plays an important role in HER2/EGFR-dependent tumor progression. Based on these data, we hypothesize that overexpression of EphA2 receptor confers intrinsic and/or acquired resistance to anti-HER2/EGFR treatment. To test this hypothesis, Specific Aim 1 will investigate the role of EphA2 in intrinsic and acquired resistance to EGFR/HER2 inhibitors, using a novel anti-EphA2 human monoclonal antibody. Specific Aim 2 will determine the molecular mechanisms through which EphA2 is activated in resistant tumor cells. Together, these studies will make significant advances towards the understanding the mechanism of drug resistance to Her2/Erb2 based therapies. Success of this project will provide a strong rationale for rapid clinical development of anti-EphA2 therapeutics for treatment of EGFR/HER2 resistant tumors, which will greatly benefit the Veteran population.