Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer

鉴定胰腺癌中直接 KRAS 抑制的耐药机制

• 批准号: 10572477
• 负责人: Andrew M Waters
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572477
• 关键词: Achievement; Address; Automobile Driving; Binding; Biological; Biology; CRISPR/Cas technology; Cancer Etiology; Cancer Model; Cell Culture Techniques; Cessation of life; Clinical; Clinical effectiveness; Codon Nucleotides; Combined Modality Therapy; Data; Development; Drug Combinations; Drug resistance; Event; Exhibits; FDA approved; Frequencies; Genetic; Goals; Growth; Impairment; KRAS2 gene; KRASG12D; Libraries; Lipids; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metabolism; Modeling; Molecular; Mutation; National Cancer Institute; Non-Small-Cell Lung Carcinoma; Observational Study; Oncogenic; Pancreatic Ductal Adenocarcinoma; Patients; Phosphotransferases; Property; Proteins; Relapse; Research; Resistance; Role; Signal Pathway; Signal Transduction; Survival Rate; System; Therapeutic; Tissues; Validation; cancer subtypes; clinical candidate; design; effective therapy; inhibitor; loss of function; mouse model; mutant; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; patient response; pharmacologic; preclinical development; relapse patients; research study; resistance mechanism; response; targeted treatment; therapy resistant; tumor; tumor microenvironment; tumorigenic

Project Summary/Abstract Pancreatic cancer is the 3rd leading cause of cancer death in the USA and the need for effective therapies is dire. KRAS is mutationally activated in ~95% of pancreatic ductal adenocarcinoma (PDAC), the major pancreatic cancer subtype. Cell culture and mouse model analyses provide strong validation for the role of mutant KRAS in the maintenance of PDAC, and the NCI has identified development of KRAS-targeted therapies as one of four major priorities for the field. Sotorasib was recently FDA-approved as the first direct KRAS inhibitor for use in KRASG12C-mutant lung cancer. However, the clinical utility of sotorasib and all other clinical candidates in PDAC is limited for two main reasons. First, sotorasib targets KRASG12C, a mutation that represents less than 2% of KRAS mutations in PDAC. KRAS inhibitors that target other KRAS mutations are currently under preclinical development. Second, patients initially responsive to KRASG12C inhibitors all soon relapse. Early studies have begun to identify genetic events that drive resistance, with expected components of RAS signaling identified in patients. However, no clear mechanisms have been identified in about half of relapsed patients. A full delineation of these mechanisms will be needed to develop effective combinations that can prolong patient response to KRAS-targeted therapies. This proposal builds on the emerging concept in understanding KRAS driver mechanisms, that different mutations cause distinct consequences on KRAS function. Consequently, there are mutation-specific driver functions that can be exploited to develop mutation-selective combination therapies. These studies focus on two lesser-studied, atypical KRAS mutations in PDAC – KRASG12R, which is unexpectedly enriched, and KRASQ61H, which is unexpectedly rare. The proposed studies will utilize direct pharmacologic inhibitors of KRASG12R and KRASQ61H in PDAC. System-wide unbiased genetic loss-of-function CRISPR/Cas9 oncogenic signaling pathway libraries will be used to identify therapeutic resistance mechanisms to KRAS inhibition. Preliminary data strongly implicate both known and novel resistance mechanisms. Finally, because KRASG12R and KRASQ61H-mutant pancreatic cancers exhibit distinct functional differences, these studies will likely identify both common and distinct resistance mechanisms to KRAS inhibition, which will lead to distinct KRAS inhibitor combination approaches. This proposal also describes the development of KrasG12R and KrasQ61H syngeneic, orthotopic pancreatic cancer mouse models. These new models will be used to define mutation- specific cancer functions, and to enable assessment of the influence of the tumor microenvironment on the consequences of KRAS inhibition alone and in combination. The overarching goals of this proposal are to further elucidate how two atypical KRAS mutations drive PDAC growth and to inform identification of combinations that can increase the clinical effectiveness of mutation-specific anti-KRAS strategies in PDAC.

项目摘要/摘要 胰腺癌是美国癌症死亡的第三主要原因，有效治疗的需求是 KRAS在约95％的胰腺导管腺癌（PDAC）中被突变激活，这是主要胰腺 癌症亚型。细胞培养和小鼠模型分析为突变KRAS的作用提供了强有力的验证 在维护PDAC和NCI中，NCI已确定靶向Kras的疗法是四种 该领域的主要优先事项。 Sotorasib最近被FDA批准为第一个用于使用的直接KRAS抑制剂 KRASG12C突变肺癌。但是，Sotorasib和PDAC中所有其他临床候选者的临床实用性 有两个主要原因有限。首先，Sotorasib靶向Krasg12c，该突变不到不到2％ PDAC中的KRAS突变。靶向其他KRAS突变的KRAS抑制剂目前处于临床前 发展。其次，最初对KRASG12C抑制剂的患者很快退休。早期研究有 开始识别驱动抗性的遗传事件，并在RAS信号的预期组件中确定 患者。但是，在大约一半的中继患者中尚未确定明确的机制。完整的描述 需要这些机制来开发有效的组合，以延长患者对 KRAS靶向疗法。该提案以理解Kras驱动程序的新兴概念为基础 机制，不同的突变会对KRAS功能产生明显的影响。因此，有 可以探索突变特异性驱动器功能，以开发突变选择性组合疗法。 这些研究集中于PDAC - KRASG12R中的两个较少研究的非典型KRAS突变，这是出乎意料的 富集和krasq61h，这是罕见的。拟议的研究将利用直接的药理学 PDAC中KRASG12R和KRASQ61H的抑制剂。系统范围无偏见的遗传丧失功能CRISPR/CAS9 致癌信号通路库将用于识别针对KRAS的治疗抗性机制 抑制。初步数据强烈暗示已知和新颖的抗性机制。最后，因为 KRASG12R和KRASQ61H突变胰腺癌暴露了不同的功能差异，这些研究将会 可能确定对KRAS抑制的常见和独特的抵抗机制，这将导致不同 KRAS抑制剂组合方法。该建议还描述了Krasg12r和Krasq61H的发展 合成性，矫形胰腺癌小鼠模型。这些新模型将用于定义突变 - 特定的癌症功能，并能够评估肿瘤微环境对 仅KRAS抑制和组合的后果。该提案的总体目标是进一步 阐明两个非典型KRAS突变如何驱动PDAC的增长并告知鉴定组合 可以提高PDAC突变特异性抗KRAS策略的临床有效性。