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

上皮-间质转化在 KRAS 突变肺癌重新布线中的作用

• 批准号: 10756186
• 负责人: Don Lynn Gibbons
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10756186
• 关键词: Address; Bioinformatics; Biometry; Cancer Etiology; Cancer Patient; Carcinoma; Clinical; Clinical Oncology; Clinical Trials; Complex; DNA Sequence Alteration; Data; Data Analyses; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Genetically Engineered Mouse; Heterogeneity; Histone Deacetylase Inhibitor; Human; Hylobates Genus; Immune; Immune checkpoint inhibitor; Immune signaling; Immunologic Tests; Immunotherapy; K-ras mouse model; KRAS2 gene; Knowledge; Lung Adenocarcinoma; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Malignant neoplasm of lung; Mediating; Mesenchymal; MicroRNAs; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Operative Surgical Procedures; PD-1/PD-L1; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Productivity; Publishing; Ras/Raf; Regulation; Research Personnel; Resected; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Translating; Tumor-infiltrating immune cells; United States; Up-Regulation; anti-PD-L1; cancer subtypes; co-clinical trial; drug development; efficacy evaluation; efficacy testing; epithelial to mesenchymal transition; human model; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; in vivo evaluation; inhibitor; kinase inhibitor; member; molecular pathology; mortality; mouse model; multidisciplinary; mutant; neoplastic cell; novel; pre-clinical; response; response biomarker; small molecule; targeted agent; treatment response; tumor; tumor heterogeneity; tumor-immune system interactions

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.

项目概要 摘要 具有特定基因组改变的非小细胞肺癌亚型的治疗取得了实质性进展 并可通过小分子激酶抑制剂进行靶向治疗。不幸的是，类似的策略并没有成功 大约 30% 的 KRAS 突变患者。同样，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受益 单代理方法。关于突变体中 MAPK 通路信号传导的调节存在知识空白 KRAS 肿瘤以及致癌信号和免疫抑制微环境之间的相互作用， 这转化为一个重大的未满足的治疗需求。 我们的多学科团队的成员（Gibbons、Heymach、Wistuba、Draetta 和 Wang）拥有 研究 KRAS 突变肺癌的生产力记录并代表小鼠建模方面的专业知识 人类肺癌、临床肿瘤学、免疫治疗、肺癌分子病理学、药物 发展和生物信息学。研究人员通过对人体的分析得出了初步数据 肺癌标本和 KRAS 突变体的临床前基因工程小鼠模型 (GEMM) NSCLC 认为肿瘤细胞的上皮间质转化 (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 抑制剂产生高度敏感性，并且 即使在突变的 KRAS 肿瘤中，间充质状态也会产生耐药性。此外，我们还发布了 microRNA-200-ZEB1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 通路信号传导突变肿瘤，2. 改变的肿瘤免疫微环境 肿瘤细胞 EMT 产生的结果赋予新免疫疗法可靶向的脆弱性，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 肺腺癌临床前模型中的从头 EMT 和获得性 MEK 抑制剂耐药性，ii) 确定 MEK 抑制剂对肿瘤免疫微环境的影响并测试其功效 它们与免疫检查点抑制剂组合可增强 KRAS 临床前模型的反应 突变型肺腺癌，以及 iii) 表征 EMT 与 MAPK 通路激活的关系 人类肺癌样本，以及抗 PD-L1/MEK 联合抑制剂敏感性/耐药性标志物 临床试验标本的治疗。