Mechanisms of YAP1-driven resistance to KRAS-G12C inhibition

YAP1 驱动的 KRAS-G12C 抑制抵抗机制

• 批准号: 10537668
• 负责人: Alexander Cole Edwards
• 金额: $ 3.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537668
• 关键词: Address; Antineoplastic Agents; Appearance; BIRC5 gene; BRAF gene; Binding; Cancer Etiology; Carbon; Cell Line; Cells; Cessation of life; Clinical; Colorectal; Colorectal Cancer; Conflict (Psychology); Cytostatics; DNA Binding Domain; Dependence; Drug resistance; Exhibits; Family; Fostering; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Glycolysis; Goals; Growth; Institutes; KRAS2 gene; Lung; MAP Kinase Gene; MAP2K1 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Maps; Mediating; Metabolism; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Mutation; Nutrient; Oncogenes; Oncogenic; Oncoproteins; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacology; Process; Publishing; Relapse; Reporting; Research; Research Personnel; Resistance; Role; Signal Transduction; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Tumor Suppressor Proteins; addiction; cancer cell; cancer therapy; career development; clinical application; clinical candidate; cytotoxic; drug development; drug discovery; genetic signature; inhibitor; mutant; overexpression; pancreatic ductal adenocarcinoma cell; research clinical testing; resistance mechanism; targeted treatment; therapeutic target; transcription factor; treatment strategy; tumor

Mutationally activated KRAS comprises the major oncogenic driver in the top three causes of cancer deaths in the US: lung (LAC), colorectal (CRC), and pancreatic ductal adenocarcinoma (PDAC). In 2021, a milestone in anti-KRAS drug discovery was achieved, with the first clinically effective direct inhibitor of KRAS approved, for the treatment of KRASG12C mutant lung cancer. However, as with essentially all targeted anti-cancer therapies, both de novo resistance and treatment-associated acquired resistance have recently been reported. As anticipated, mutations that reactivate RAS and RAS effector signaling through the RAF-MEK-ERK mitogen- activated protein kinase signaling network (e.g., activating mutations in BRAF, MEK1) were identified in LAC and CRC patients treated with KRASG12C selective inhibitors (G12Ci), and combinations that concurrently target these resistance mechanisms are now under clinical evaluation. However, no genetic mechanisms were identified in up to 50% of patients who relapsed on G12Ci treatment. To address possible ERK MAPK-independent resistance mechanisms, my studies have identified and validated the downstream target of the Hippo tumor suppressor pathway, the YAP1 transcriptional coactivator and oncoprotein, as a driver of resistance to G12Ci- mediated growth suppression. Consistent with previous studies that established the ability of YAP1 activation to overcome addiction to mutant KRAS, my preliminary analyses demonstrated that ectopic overexpression of wild- type or activated YAP1 drives resistance to G12Ci treatment in KRASG12C mutant LAC, CRC and PDAC cell lines. This finding establishes the rationale and foundation for my research goal: to determine the mechanistic basis for YAP1-mediated resistance to G12Ci treatment. I hypothesize that identification of YAP1-driven resistance mechanisms will establish combinations of pharmacologic inhibitors that can enhance the long-term anti-tumor efficacy of G12Ci and other KRAS-targeted therapies. I have developed three aims to address the mechanisms by which YAP1 drives resistance. First, I will determine the role of the TEAD transcription factors in YAP1-driven KRAS-independence. These studies may validate the clinical application of TEAD inhibitors for the treatment of KRAS-mutant PDAC and other cancers. Second, I will identify YAP1- regulated genes that sustain KRAS-independent growth, in support of a model where YAP1 overcomes KRAS- addiction by restoring expression of key KRAS-regulated genes. Finally, I will identify KRAS-regulated metabolic processes that are both sustained by YAP1 activation and important for PDAC growth. Taken together, my studies may validate an important driver of resistance to all KRAS-targeted therapies and define therapeutic approaches to overcome YAP1-driven drug resistance. These studies will require my application of a diverse spectrum of experimental approaches, advance my understanding of key steps in anti-cancer drug development, and foster my career development as an independent cancer researcher.

突变激活的KRAS是癌症死亡的三大原因中的主要致癌驱动因素， 美国：肺（LAC）、结肠直肠（CRC）和胰腺导管腺癌（PDAC）。2021年，一个里程碑， 实现了抗KRAS药物的发现，第一个临床有效的KRAS直接抑制剂获得批准，用于 KRASG 12 C突变型肺癌的治疗。然而，与基本上所有靶向抗癌疗法一样， 最近报道了新生耐药性和治疗相关的获得性耐药性。作为 预期，通过RAF-MEK-ERK有丝分裂原重新激活RAS和RAS效应子信号传导的突变- 活化的蛋白激酶信号网络（例如，在LAC中鉴定了BRAF、MEK 1中的激活突变）， 用KRASG 12 C选择性抑制剂（G12 Ci）和同时靶向这些抑制剂的组合治疗的CRC患者 目前正在对耐药机制进行临床评估。然而，没有发现遗传机制， 高达50%的患者在G12 Ci治疗后复发。为了解决可能的ERK MAPK非依赖性 耐药机制，我的研究已经确定并验证了河马肿瘤的下游靶点 抑制途径，YAP 1转录辅激活因子和癌蛋白，作为对G12 Ci-1耐药的驱动因素， 介导的生长抑制。与先前的研究一致，这些研究确定了YAP 1激活的能力， 克服对突变型KRAS的成瘾，我的初步分析表明，野生型KRAS的异位过表达， 型或激活的YAP 1驱动KRASG 12 C突变体LAC、CRC和PDAC细胞对G12 Ci处理的抗性 线这一发现为我的研究目标建立了理论基础和基础： YAP 1介导的对G12 Ci治疗的抗性的基础。我假设识别YAP 1驱动的 耐药机制将建立药理学抑制剂的组合，可以增强 G12 Ci和其他KRAS靶向治疗的长期抗肿瘤疗效。我制定了三个目标， 解决YAP 1驱动阻力的机制。首先，我将确定TEAD的作用 转录因子在YAP 1驱动的KRAS独立性。这些研究可能会验证的临床应用 用于治疗KRAS突变型PDAC和其他癌症的TEAD抑制剂。其次，我将识别YAP 1- 维持KRAS非依赖性生长的调节基因，支持YAP 1克服KRAS的模型， 通过恢复关键KRAS调节基因的表达来治疗成瘾。最后，我将确定KRAS调节的代谢 这些过程都是由YAP 1激活维持的，对PDAC生长很重要。总的来说，我的 研究可能会验证对所有KRAS靶向治疗产生耐药性的重要驱动因素，并定义治疗方法。 克服YAP 1驱动的耐药性的方法。这些研究将需要我应用各种 实验方法的光谱，提高我对抗癌药物开发关键步骤的理解， 并促进我作为一名独立癌症研究人员的职业发展。