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

项目总结摘要 在含有特定基因组改变的非小细胞肺癌亚群中已取得实质性的治疗进展 并以小分子激酶抑制剂为靶点。不幸的是，类似的策略并未成功。 约30%的突变KRAS患者。同样，PD-1/PD-L1轴的免疫检查点抑制物 为约20%的非小细胞肺癌患者提供持久的反应，但大多数患者并未从中受益 单一代理方法。突变体中MAPK信号通路的调控存在知识空白 KRAS肿瘤以及致癌信号和免疫抑制微环境之间的相互作用， 这就转化为一个重大的未得到满足的治疗需求。 我们多学科团队的成员(Gibbons，Heymach，Wistuba，Draetta和Wang) 在研究KRAS突变肺癌方面的卓有成效的记录，并代表了小鼠模型方面的专业知识 人类肺癌，临床肿瘤学，免疫疗法，肺癌分子病理学，药物 发展和生物信息学。研究人员从对人类的分析中开发出了初步数据 肺癌标本和KRAS突变的临床前基因工程小鼠模型 NSCLC认为肿瘤细胞的上皮-间充质转化(EMT)状态对其治疗至关重要 对MEK抑制剂的反应，上皮状态对MEK抑制剂和 间充质状态产生抵抗，即使在突变的KRAS肿瘤中也是如此。此外，我们已经公布了 MicroRNA-200-ZEB1轴调节EMT、肿瘤免疫微环境及后续反应 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 抑制MAPK信号转导的突变型肿瘤2.肿瘤免疫微环境的改变 由肿瘤细胞引起的EMT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 新生EMT与临床前肺腺癌模型对MEK抑制剂的获得性耐药 检测MEK抑制剂对肿瘤免疫微环境的影响及检测其疗效 它们与免疫检查点抑制剂联合应用可增强KRAS临床前模型的反应 突变型肺腺癌，以及III)EMT与MAPK通路激活之间的关系 人肺癌标本与联合抗PD-L1/MEK抑制剂敏感性/耐药性标志物的研究 临床试验标本中的治疗。

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.