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是导致中国癌症死亡的前三大致癌因素 美国：肺癌(LAC)、结直肠癌(CRC)和胰腺导管腺癌(PDAC)。2021年，这是 实现了抗KRAS药物的发现，批准了第一个临床有效的KRAS直接抑制剂，用于 KRASG12C突变肺癌的治疗然而，与基本上所有的靶向抗癌疗法一样， 新发耐药和治疗相关的获得性耐药最近都有报道。AS 预计，通过RAF-MEK-ERK丝裂原重新激活RAS和RAS效应器信号的突变- 激活的蛋白激酶信号网络(例如，BRAF、MEK1的激活突变)在LAC和 使用KRASG12C选择性抑制剂(G12Ci)和同时针对这些药物的联合治疗的结直肠癌患者 耐药机制目前正在进行临床评估。然而，没有发现任何遗传机制在 在接受G12Ci治疗的复发患者中，高达50%。以解决可能的ERK MAPK独立问题 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，YAP1转录辅助激活因子和癌蛋白，作为G12Ci抗性的驱动因素。 中介生长抑制。与先前建立了YAP1激活能力的研究一致 克服对突变KRAS的依赖，我的初步分析表明，野生型KRAS的异位过度表达- YAP1类型或激活促进KRASG12C突变LAC、CRC和PDAC细胞对G12Ci治疗的耐药性 台词。这一发现为我的研究目标奠定了理论基础和基础：确定 YAP1介导的对G12Ci治疗的抗性基础。我假设由YAP1驱动的 耐药机制将建立药物抑制剂的组合，可以增强 G12Ci和其他KRAS靶向治疗的长期抗肿瘤疗效。我制定了三个目标来 阐述YAP1驱动阻力的机制。首先，我将确定Tead的角色 YAP1驱动的KRAS-独立性中的转录因子。这些研究可能会验证其临床应用。 TEAD抑制剂，用于治疗KRAS突变的PDAC和其他癌症。第二，我将确定YAP1- 维持KRAS独立生长的受调控基因，支持YAP1克服KRAS的模型- 通过恢复KRAS调节的关键基因的表达而成瘾。最后，我将确定KRAS调节的代谢 既由YAP1激活维持，又对PDAC生长重要的过程。加在一起，我的 研究可能证实对所有KRAS靶向治疗的抵抗的一个重要驱动因素，并定义治疗 克服YAP1驱动的耐药性的方法。这些研究将需要我应用不同的 实验方法的光谱，加深了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。