Mechanisms of YAP1-driven resistance to KRAS-G12C inhibition

YAP1 驱动的 KRAS-G12C 抑制抵抗机制

• 批准号: 10675482
• 负责人: Alexander Cole Edwards
• 金额: $ 3.88万
• 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/10675482
• 关键词: Address; Antineoplastic Agents; Appearance; Autophagocytosis; BIRC5 gene; BRAF gene; Binding; Cancer Etiology; Cancer Model; Carbon; Cell Line; Cells; Cessation of life; Clinical; Colorectal; Colorectal Cancer; Combined Modality Therapy; Cytostatics; DNA Binding Domain; Dependence; Drug resistance; Exhibits; Family; Fostering; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Glycolysis; Goals; Growth; 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; Overlapping Genes; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; 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; pharmacologic; research clinical testing; resistance mechanism; targeted treatment; therapeutic target; transcription factor; treatment strategy; tumor; tumor metabolism

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包括癌症死亡的前三名主要驱动因素 美国：肺（LAC），结直肠（CRC）和胰腺导管腺癌（PDAC）。 2021年，一个里程碑 通过批准KRAS的第一个有效的直接抑制剂，实现了抗KRAS药物发现 Krasg12c突变肺癌的治疗。但是，与基本上所有有针对性的抗癌疗法一样， 最近已经报道了从头耐药性和与治疗相关的获得性抗性。作为 预期的是，通过RAF-MEK-ERK促丝分裂原-ERK-MEK-ERK-ERK-ERK-ERK重新激活RAS和RAS效应子信号的突变 在LAC和 用KRASG12C选择性抑制剂（G12CI）治疗的CRC患者以及同时针对这些抑制剂的组合 电阻机制现在正在临床评估下。但是，未在 接受G12CI治疗的患者中，多达50％的患者。解决可能的ERK MAPK独立 电阻机制，我的研究已经确定并验证了河马肿瘤的下游靶标 抑制途径，YAP1转录共激活剂和癌蛋白，作为对G12CI-的抗性的驱动力 介导的生长抑制。与以前确定YAP1激活能力的研究一致 克服对突变kras的成瘾，我的初步分析表明，野生的异位过表达 类型或活化的YAP1在KRASG12C突变体LAC，CRC和PDAC细胞中驱动对G12CI处理的抵抗力 线。这一发现确定了我的研究目标的基本原理和基础：确定机制 YAP1介导的对G12CI治疗的抗性的基础。我假设对YAP1驱动的识别 耐药机制将建立可以增强的药理学抑制剂组合 G12CI和其他靶向KRAS的疗法的长期抗肿瘤功效。我已经开发了三个目标 解决YAP1驱动阻力的机制。首先，我将确定tead的作用 YAP1驱动的KRAS独立性中的转录因子。这些研究可能会验证 将抑制剂用于治疗KRAS突变PDAC和其他癌症。其次，我将确定yap1- 在支持Yap1克服KRAS- 通过恢复关键KRAS调节基因的表达来成瘾。最后，我将确定受KRAS调节的代谢 YAP1激活所维持的过程均对PDAC增长很重要。总之，我 研究可能会验证对所有靶向KRAS靶向疗法的耐药性的重要驱动力并定义治疗方法 克服YAP1驱动的耐药性的方法。这些研究将需要我应用多样的 实验方法的范围，促进我对抗癌药物开发的关键步骤的理解， 并促进我作为独立癌症研究员的职业发展。