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

EphA2 RTK 在肿瘤对 EGFR/HER2 抑制剂耐药中的作用

• 批准号: 7796394
• 负责人: Jin Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796394
• 关键词: Age; Antibodies; Antineoplastic Agents; Biochemical; Breast; Breast Adenocarcinoma; Breast Cancer Cell; Breast Melanoma; Cancer Patient; Cancer cell line; Cause of Death; Cell Line; Cells; Clinic; Clinical; Clinical Research; Combined Modality Therapy; Complex; Data; Development; Disease; Disease-Free Survival; Drug Delivery Systems; Drug resistance; EGFR inhibition; ERBB2 gene; Eph Family Receptors; EphA Receptors; EphA2 Receptor; Epidermal Growth Factor Receptor; ErbB Receptor Family Protein; Exhibits; FDA approved; Fluorescence Resonance Energy Transfer; Gefitinib; Glioblastoma; Head and Neck Squamous Cell Carcinoma; Homologous Gene; Human; In Vitro; Laboratories; Large Intestine Carcinoma; Link; MAP Kinase Gene; Malignant Neoplasms; Mediating; Molecular; Monitor; Monoclonal Antibodies; Mouse Mammary Tumor Virus; Non-Small-Cell Lung Carcinoma; Oncogene ErbB2; Ovarian Carcinoma; Pathway interactions; Patients; Phosphorylation; Play; Population; Principal Investigator; Prostate carcinoma; Protein Tyrosine Kinase; Rattus; Reporter; Reporting; Research; Resistance; Roche brand of trastuzumab; Role; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Transgenic Model; Trastuzumab; Tyrosine Kinase Inhibitor; Up-Regulation; Vascular Endothelial Growth Factors; Veterans; angiogenesis; base; bladder Carcinoma; cancer cell; cancer therapy; cancer type; design; human monoclonal antibodies; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; malignant breast neoplasm; mammary epithelium; member; neoplastic cell; new therapeutic target; novel; overexpression; preclinical study; programs; public health relevance; receptor expression; research study; resistance mechanism; rho GTP-Binding Proteins; small molecule; success; tumor; tumor initiation; tumor progression; tumorigenesis

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.

描述（由申请人提供）： 癌症分子靶向疗法的开发和应用的最新进展产生了有希望的新疗法。然而，实现无病生存的一个主要障碍是耐药性。这项研究的长期目标是研究耐药机制并针对耐药肿瘤进行治疗。该应用将具体确定 EphA2 受体酪氨酸激酶在 EGFR/HER2 抑制剂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) ErbB 家族，对于肿瘤的发生和转移进展至关重要。已经开发了几种针对 EGFR 和 HER2/ErbB2 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）。尽管具有初步疗效，但临床上经常观察到内在的和获得性的耐药性。我们发现抗 EGFR/HER2 疗法耐药的机制之一是 EphA2（Eph 家族 RTK 成员）的上调。 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 表达水平与肿瘤恶性程度和患者生存率相关。我们最近报道，EphA2 缺陷会损害过度表达 ErbB2 癌基因的肿瘤的肿瘤发生和转移进展。生化分析表明，EphA2 与 HER2 或 EGFR 形成复合物，并促进 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 依赖性肿瘤进展中发挥重要作用。基于这些数据，我们假设 EphA2 受体的过度表达赋予抗 HER2/EGFR 治疗的内在和/或获得性耐药性。为了检验这一假设，Specific Aim 1 将使用一种新型抗 EphA2 人单克隆抗体来研究 EphA2 在 EGFR/HER2 抑制剂内在和获得性耐药中的作用。具体目标 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 的疗法的耐药机制方面取得重大进展。该项目的成功将为用于治疗 EGFR/HER2 耐药肿瘤的抗 EphA2 疗法的快速临床开发提供强有力的依据，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。退伍军人事务部患者每年约有 35,000 例新发癌症病例，估计退伍军人癌症患者总数为 175,000 人，而且随着退伍军人人口老龄化，这一数字还将增加。尽管癌症治疗的最新进展产生了有希望的新疗法，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（FDA 批准的两种抗癌药物）的耐药机制。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受益匪浅。