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.

项目概要/摘要 胰腺癌是美国癌症死亡的第三大原因，因此需要有效的治疗方法 KRAS 在大约 95% 的胰腺导管腺癌 (PDAC)（主要的胰腺癌）中被突变激活。 癌症亚型。细胞培养和小鼠模型分析为突变型 KRAS 的作用提供了强有力的验证。 在维持 PDAC 方面，NCI 已将 KRAS 靶向疗法的开发确定为四种疗法之一 Sotorasib 最近被 FDA 批准作为第一个用于该领域的直接 KRAS 抑制剂。 然而，Sotorasib 和所有其他临床候选药物在 PDAC 中的临床应用。 首先，sotorasib 的目标是 KRASG12C，这种突变只占不到 2%。 针对其他 KRAS 突变的 PDAC 中的 KRAS 突变目前正处于临床前阶段。 其次，早期研究发现最初对 KRASG12C 抑制剂有反应的患者很快就会复发。 开始识别驱动耐药性的遗传事件，其中识别出 RAS 信号传导的预期成分 然而，在大约一半的复发患者中尚未确定明确的机制。 需要利用这些机制来开发有效的组合，以延长患者对药物的反应 KRAS 靶向疗法基于理解 KRAS 驱动程序的新兴概念。 研究表明，不同的突变会对 KRAS 功能产生不同的影响。 突变特异性驱动功能可用于开发突变选择性联合疗法。 这些研究重点关注 PDAC 中两种较少研究的非典型 KRAS 突变——KRASG12R，这是出乎意料的 富集的KRASQ61H，这是出乎意料的罕见。拟议的研究将利用直接药理学。 PDAC 中 KRASG12R 和 KRASQ61H 的抑制剂。 致癌信号通路文库将用于识别 KRAS 的治疗耐药机制 最后，初步数据强烈暗示了已知的和新的耐药机制。 KRASG12R 和 KRASQ61H 突变型胰腺癌表现出明显的功能差异，这些研究将 可能会识别出对 KRAS 抑制的常见和独特的耐药机制，这将导致不同的 该提案还描述了 KrasG12R 和 KrasQ61H 的开发。 这些新模型将用于定义突变-同基因原位胰腺癌小鼠模型。 特定的癌症功能，并能够评估肿瘤微环境对癌症的影响 单独和组合 KRAS 抑制的后果 该提案的总体目标是进一步推进。 阐明两种非典型 KRAS 突变如何驱动 PDAC 生长，并为识别组合提供信息 可以提高 PDAC 突变特异性抗 KRAS 策略的临床有效性。