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

描述（由申请人提供）： 癌症分子靶向治疗的发展和应用的最新进展产生了有前途的新治疗方法。然而，实现无病生存的一个主要障碍是耐药性。本研究的长期目标是研究耐药机制和耐药肿瘤的治疗靶点。本申请将具体确定EphA 2受体酪氨酸激酶在EGFR/HER 2抑制剂的内在和获得性耐药性中的作用。 EGFR和HER 2属于ErbB受体酪氨酸激酶（RTK）家族，对肿瘤的发生和转移进展至关重要。已经开发了几种靶向EGFR和HER 2/ErbB 2的治疗策略，包括激酶抑制剂如易瑞沙（吉非替尼）和抗体如赫赛汀（曲妥珠单抗）。尽管最初的疗效，内在的和获得性耐药性是经常观察到的临床。我们发现，抗EGFR/HER 2治疗的抗性机制之一是Eph家族RTK成员EphA 2的上调。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，EphA 2缺陷损害肿瘤的启动和转移进展的肿瘤过度表达的ErbB 2癌基因。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的治疗性治疗敏感，表明EphA 2在HER 2/EGFR依赖性肿瘤进展中起重要作用。基于这些数据，我们假设EphA 2受体的过表达赋予抗HER 2/EGFR治疗的内在和/或获得性抗性。为了验证这一假设，Specific Aim 1将使用新型抗EphA 2人单克隆抗体研究EphA 2在EGFR/HER 2抑制剂的内在和获得性耐药性中的作用。特异性目标2将确定EphA 2在抗性肿瘤细胞中被激活的分子机制。总之，这些研究将在理解对基于Her 2/Erb 2的疗法的耐药性机制方面取得重大进展。该项目的成功将为快速临床开发用于治疗EGFR/HER 2耐药肿瘤的抗EphA 2治疗剂提供强有力的理论基础，这将极大地造福退伍军人群体。 公共卫生相关性： 癌症是退伍军人死亡的第二大原因。每年退伍军人管理局患者中约有35，000例新癌症病例，估计退伍军人癌症患者总数为175，000例，并且随着退伍军人人口的老龄化，这一数字还将增加。尽管癌症治疗的最新进展已经产生了有希望的新治疗方法，但无病生存的主要障碍是耐药性。本申请中提出的研究旨在剖析肿瘤对吉非替尼和曲妥珠单抗（两种FDA批准的抗癌药物）的耐药性机制。这些研究的成功将允许合理设计克服耐药性的联合疗法，这将使退伍军人群体大大受益。

DESCRIPTION (provided by applicant): 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 up-regulation of EphA2, a member of Eph family RTKs. EphA2 has been linked to many types of cancer, including NSCLC, glioblastoma, 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 over-expressing 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. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death among Veterans. Approximately 35,000 new cases of cancer occur in VA patients each year with a total estimated number of 175,000 Veteran cancer patients, and this number will increase as the Veteran population ages. Although recent advances in cancer therapeutics have generated promising new treatments, a major obstacle for disease-free survival is drug resistance. Studies proposed in this application are aimed at dissecting mechanisms of tumor resistance to Gefitinib and Trastuzumab, two FDA approved anti-cancer agents. Success of these studies will allow rational design of combination therapies that overcome drug resistance, which will benefit the Veteran population substantially.