Mechanisms of YAP1-driven resistance to KRAS-G12C inhibition

YAP1 驱动的 KRAS-G12C 抑制抵抗机制

基本信息

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
项目类别：
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

项目摘要

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 是导致癌症死亡的三大原因中的主要致癌驱动因素美国：肺癌（LAC）、结直肠癌（CRC）和胰腺导管腺癌（PDAC）。 2021年，具有里程碑意义实现抗 KRAS 药物发现，首个临床有效的 KRAS 直接抑制剂获批，用于 KRASG12C突变肺癌的治疗。然而，与基本上所有靶向抗癌疗法一样，最近报道了新发耐药和与治疗相关的获得性耐药。作为预期的，通过 RAF-MEK-ERK 有丝分裂原重新激活 RAS 和 RAS 效应信号传导的突变在 LAC 和使用 KRASG12C 选择性抑制剂 (G12Ci) 以及同时针对这些抑制剂的组合治疗的 CRC 患者耐药机制目前正在临床评估中。然而，尚未发现遗传机制高达 50% 的患者在接受 G12Ci 治疗后复发。解决可能与 ERK MAPK 无关的问题耐药机制，我的研究已经确定并验证了 Hippo 肿瘤的下游靶点抑制途径、YAP1 转录辅激活因子和癌蛋白，作为 G12Ci- 耐药性的驱动因素介导的生长抑制。与之前建立 YAP1 激活能力的研究一致为了克服对突变型 KRAS 的成瘾，我的初步分析表明，野生型的异位过度表达类型或激活的 YAP1 驱动 KRASG12C 突变 LAC、CRC 和 PDAC 细胞对 G12Ci 治疗的耐药性线。这一发现为我的研究目标奠定了基本原理和基础：确定机制 YAP1 介导的 G12Ci 治疗耐药性的基础。我假设 YAP1 驱动的识别耐药机制将建立药物抑制剂的组合，可以增强 G12Ci 和其他 KRAS 靶向疗法的长期抗肿瘤功效。我制定了三个目标解决 YAP1 驱动抵抗的机制。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 PDAC 和其他癌症。其次，我将识别 YAP1- 维持不依赖 KRAS 的生长的调节基因，支持 YAP1 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既由 YAP1 激活维持，又对 PDAC 生长很重要。综合起来，我的研究可能会验证所有 KRAS 靶向疗法耐药性的重要驱动因素，并定义治疗方法克服 YAP1 驱动的耐药性的方法。这些研究需要我应用多种方法一系列实验方法，加深我对抗癌药物开发关键步骤的理解，并促进我作为独立癌症研究员的职业发展。