Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC

总结/摘要： 肺癌是全球最常见的癌症，也是美国癌症相关死亡的主要原因。 EGFR酪氨酸激酶抑制剂（TKI）可改善非小细胞肺癌患者的预后 （NSCLC）与激活EGFR突变（EGFRMT），但许多肿瘤不响应，大多数会 在9-12个月内产生耐药性。奥希替尼是第三代EGFR TKI，最近已进入一线治疗 EGFRMT NSCLC治疗，不考虑T790 M突变，但患者的治疗选择仍然有限 会产生抗药性肿瘤本提案描述了评价MERTK抑制的临床前研究 受体酪氨酸激酶联合EGFR TKI治疗EGFRMT NSCLC，包括一个阶段 1b临床试验，以测试这些患者的组合。70%的NSCLC具有异常高水平的MERTK 并且抑制肿瘤细胞降低小鼠中的肿瘤生长。MERTK也存在于肿瘤的免疫细胞中 微环境，在那里它抑制抗肿瘤先天免疫反应。我们的数据表明， 重新编程免疫系统来攻击肿瘤。MERTK也可介导EGFR耐药 TKI，包括奥希替尼，表明MERTK抑制将使EGFRMT肿瘤对以下治疗敏感： EGFR TKI，并可能减少耐药性的发展。这些数据将MERTK确定为NSCLC的新靶点 并暗示MERTK靶向抑制剂是一个前所未有的机会， 在单一药物中的治疗方法，导致（1）直接杀死肿瘤细胞，（2）激活抗肿瘤先天性 免疫力，和（3）对EGFR TKI治疗的敏感性增加。为了测试这个想法并生产出可以 用于人体时，我们开发了MERTK选择性TKI，包括MRX-2843。MRX-2843有效， 在小鼠中进行单药治疗，并增加EGFRMT NSCLC细胞对EGFR TKI的敏感性。拟议的研究 使用MRX-2843和其他MERTK抑制剂研究MERTK和EGFR联合抑制的影响 在EGFRMT NSCLC的细胞培养物和小鼠模型中，包括肿瘤细胞直接植入 肺、来源于新鲜患者样品的模型和肿瘤细胞转移的模型。mertk基因敲除的小鼠- 还将用于确定MERTK抑制在肿瘤微环境中的作用及其影响 对抗肿瘤免疫的影响。其他研究将确定免疫系统中的MERTK抑制如何导致 肿瘤排斥最后，该项目的一个亮点是MRX-2843和奥希替尼在 晚期EGFRMT NSCLC患者，一项包括2个扩展队列的研究， 以及治疗后肿瘤活检和血液样本，以评价MERTK抑制的生物标志物，包括 MRX-2843给药后免疫功能的变化。临床试验的结果和 相关研究将提供更有效和毒性更小的治疗选择，从而优化护理， 改善EGFRMT NSCLC患者的生存率。

Summary/Abstract: Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the US. EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients who have non-small cell lung cancer (NSCLC) with an activating EGFR mutation (EGFRMT), but many tumors do not respond and most that do will become resistant in 9-12 months. Osimertinib, a 3rd generation EGFR TKI, has recently advanced to frontline therapy for EGFRMT NSCLC, irrespective of T790M mutation, but treatment options remain limited for patients who develop resistant tumors. This proposal describes preclinical studies to evaluate inhibition of the MERTK receptor tyrosine kinase in combination with EGFR TKIs for treatment of EGFRMT NSCLC and includes a phase 1b clinical trial to test the combination in these patients. 70% of NSCLCs have abnormally high levels of MERTK and inhibition in tumor cells decreases tumor growth in mice. MERTK is also present in immune cells in the tumor microenvironment, where it suppresses the anti-tumor innate immune response. Our data suggest that inhibition of MERTK reprograms the immune system to attack the tumor. MERTK can also mediate resistance to EGFR TKIs, including osimertinib, suggesting that MERTK inhibition will sensitize EGFRMT tumors to treatment with EGFR TKIs and may decrease development of resistance. These data identify MERTK as a new target in NSCLC and implicate MERTK-targeted inhibitors as an unprecedented opportunity to provide a three-pronged therapeutic approach in a single drug, leading to (1) direct tumor cell killing, (2) activation of anti-tumor innate immunity, and (3) increased sensitivity to EGFR TKI therapy. To test this idea and generate drugs that can be used in humans, we developed MERTK-selective TKIs, including MRX-2843. MRX-2843 is effective as monotherapy in mice and increases sensitivity to EGFR TKIs in EGFRMT NSCLC cells. The proposed studies use MRX-2843 and other MERTK inhibitors to investigate the effects of combined MERTK and EGFR inhibition in cell culture and mouse models of EGFRMT NSCLC, including models with tumor cells implanted directly in the lung, models derived from fresh patient samples, and models of tumor cell metastasis. Mice with mertk knock- out will also be used to determine the effects of MERTK inhibition in the tumor microenvironment and its impact on anti-tumor immunity. Additional studies will determine how MERTK inhibition in the immune system leads to tumor rejection. Finally, a highlight of this project is the dedicated clinical trial of MRX-2843 and osimertinib in patients with advanced EGFRMT NSCLC, a study that includes 2 expansion cohorts with paired collection of pre- and post-treatment tumor biopsies and blood samples to evaluate biomarkers of MERTK inhibition, including changes in immune function, following treatment with MRX-2843. The results from the clinical trial and associated studies will provide more effective and less toxic treatment options leading to optimized care and improved survival for patients with EGFRMT NSCLC.