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

描述(由申请人提供)： 最近在分子靶向治疗癌症方面的发展和应用取得了进展，产生了有希望的新治疗方法。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探讨耐药机制和靶向耐药肿瘤的治疗。这一应用将专门确定EphA2受体酪氨酸激酶在对EGFR/HER2抑制剂的内在和获得性耐药中的作用。EGFR和HER2属于受体酪氨酸激酶(RTK)的ErbB家族，在肿瘤的发生和转移过程中起关键作用。针对EGFR和HER2/ErbB2的几种治疗策略已经开发出来，包括激酶抑制剂如易瑞沙(Gefitinib)和抗体如Herceptin(曲妥珠单抗)。尽管有初步疗效，但临床上经常观察到固有和获得性耐药。我们发现抵抗抗EGFR/HER2治疗的机制之一是上调Eph家族RTK成员EphA2的表达。EphA2与许多类型的癌症有关，包括非小细胞肺癌、胶质母细胞瘤、黑色素瘤、乳腺癌、结直肠癌、膀胱癌、前列腺癌和卵巢癌。此外，EphA2的表达水平与肿瘤的恶性程度和患者的生存有关。我们最近报道，在过度表达ErbB2癌基因的肿瘤中，EphA2缺乏会损害肿瘤的起始和转移进展。生化分析表明，EphA2与HER2或EGFR形成复合体，促进MAPK和Rho GTPase的激活。此外，MMTV-Neu肿瘤对EphA2的治疗敏感，表明EphA2在HER2/EGFR依赖的肿瘤进展中发挥重要作用。基于这些数据，我们假设EphA2受体的过度表达导致了对抗HER2/EGFR治疗的固有和/或获得性抵抗。为了验证这一假设，特殊目的1将使用一种新的抗EphA2人类单抗来研究EphA2在对EGFR/HER2抑制剂的内在和获得性耐药中的作用。特异性目标2将确定EphA2在耐药肿瘤细胞中被激活的分子机制。总之，这些研究将在理解基于Her2/ERB2的治疗的耐药机制方面取得重大进展。该项目的成功将为快速开发用于治疗EGFR/HER2耐药肿瘤的抗EphA2疗法提供强有力的基础，这将极大地造福于退伍军人群体。

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.