The Role of Epithelial-Mesenchymal Transition in Re-Wiring KRAS Mutant Lung Cancer

项目摘要 在携带特定基因组改变的NSCLC亚群中，已取得了实质性的治疗进展 并且可被小分子激酶抑制剂靶向。不幸的是，类似的策略一直不成功 约30%的KRAS突变患者。类似地，PD-1/PD-L1轴的免疫检查点抑制剂 为约20%的NSCLC患者提供持久缓解，但大多数患者并未从中获益 单代理方法。目前对突变体中MAPK信号通路的调控还存在认识上的空白， KRAS肿瘤，以及致癌信号与免疫抑制微环境之间的相互作用， 这转化为一个主要的未满足的治疗需求。 我们的多学科团队成员（Gibbons，Heymach，Wistuba，Draetta和Wang）有一个 在研究KRAS突变型肺癌方面的生产力记录，并代表了小鼠建模方面的专业知识 肺癌分子病理学，临床肿瘤学，免疫治疗，药物 发展和生物信息学。研究人员已经从对人类的分析中获得了初步数据。 肺癌标本和KRAS突变的临床前遗传工程小鼠模型（GEMM） 非小细胞肺癌的上皮间质转化（EMT）状态是其治疗的关键 对MEK抑制剂的反应，上皮状态对MEK抑制剂产生深刻的敏感性， 间充质状态产生耐药性，即使在突变的KRAS肿瘤中。此外，我们已公布， microRNA-200-ZEB 1轴调节EMT，肿瘤的免疫微环境和随后的反应 免疫检查点抑制剂 根据初步数据，我们假设：1。肿瘤细胞EMT在KRAS中产生异质性 通过抑制MAPK通路信号传导的突变体肿瘤，2.肿瘤免疫微环境的改变 由肿瘤细胞EMT产生的免疫缺陷为新的免疫疗法提供了靶向的脆弱性，3.组合 免疫检查点抑制剂和信号传导通路抑制剂将提供有效的互补， 突变型KRAS NSCLC的靶向策略。我们将通过以下方式解决这些假设：i）评估 肺腺癌临床前模型中对MEK抑制剂的新发和获得性耐药性中的EMT，ii） 确定MEK抑制剂对肿瘤免疫微环境的影响并测试MEK抑制剂的功效。 它们与免疫检查点抑制剂组合以增强KRAS临床前模型中的应答 突变型肺腺癌，和iii）表征EMT与MAPK途径活化的关系， 人肺癌样品和对组合抗PD-L1/MEK抑制剂的敏感性/抗性的标志物 临床试验样本中的治疗。

PROJECT SUMMARY ABSTRACT Substantial therapeutic advances have been made in NSCLC subsets harboring specific genomic alterations and targetable with small molecule kinase inhibitors. Unfortunately, a similar strategy has been unsuccessful for the ~30% of patients with mutated KRAS. Similarly, immune checkpoint inhibitors of the PD-1/PD-L1 axis provide durable response to ~20% of NSCLC patients, but the majority of patients do not benefit from this single-agent approach. There is a knowledge gap about the regulation of MAPK pathway signaling in mutant KRAS tumors, and the interplay between oncogenic signaling and the immunosuppressive microenvironment, which translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons, Heymach, Wistuba, Draetta and Wang) have a track record of productivity in studying KRAS mutant lung cancer and represent expertise in mouse modeling of human lung cancer, clinical oncology, immunotherapy, molecular pathology of lung cancer, drug development and bioinformatics. The Investigators have developed preliminary data from analysis of human lung cancer specimens and preclinical Genetically Engineered Mouse Models (GEMMs) of KRAS mutant NSCLC that the epithelial-mesenchymal transition (EMT) status of tumor cells is critical to their therapeutic response to MEK inhibitors, with the epithelial state producing profound sensitivity to MEK inhibitors and the mesenchymal state producing resistance, even in mutant KRAS tumors. Further, we have published that the microRNA-200-ZEB1 axis regulates EMT, the immune microenvironment of tumors and subsequent response to immune checkpoint inhibitors. Based upon preliminary data, we hypothesize that: 1. Tumor cell EMT produces heterogeneity in KRAS mutant tumors by suppressing MAPK pathway signaling, 2. The altered tumor immune microenvironment resulting from tumor cell EMT confers targetable vulnerabilities to new immune therapies, 3. Combination immune checkpoint inhibitors and signaling pathway inhibitors will provide an effective complementary targeting strategy for mutant KRAS NSCLC. We will address these hypotheses by: i) evaluating the role of EMT in de novo and acquired resistance to MEK inhibitors in preclinical models of lung adenocarcinoma, ii) determining the effects of MEK inhibitors on the tumor immune microenvironment and testing the efficacy of their combination with immune checkpoint inhibitors to enhance response in preclinical models of KRAS mutant lung adenocarcinoma, and iii) characterizing the relationship of EMT to MAPK pathway activation in human lung cancer samples, and the markers of sensitivity/resistance to combination anti-PD-L1/MEK inhibitor treatment in clinical trial specimens.