Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer
Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer
批准号:
10572477
负责人:
Andrew M Waters
金额:
$19.19万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-15 至 2026-05-31
关键词:
AchievementAddressAutomobile DrivingBindingBiologicalBiologyCRISPR/Cas technologyCancer EtiologyCancer ModelCell Culture TechniquesCessation of lifeClinicalClinical effectivenessCodon NucleotidesCombined Modality TherapyDataDevelopmentDrug CombinationsDrug resistanceEventExhibitsFDA approvedFrequenciesGeneticGoalsGrowthImpairmentKRAS2 geneKRASG12DLibrariesLipidsMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMetabolismModelingMolecularMutationNational Cancer InstituteNon-Small-Cell Lung CarcinomaObservational StudyOncogenicPancreatic Ductal AdenocarcinomaPatientsPhosphotransferasesPropertyProteinsRelapseResearchResistanceRoleSignal PathwaySignal TransductionSurvival RateSystemTherapeuticTissuesValidationcancer subtypesclinical candidatedesigneffective therapyinhibitorloss of functionmouse modelmutantnovelpancreatic cancer patientspancreatic ductal adenocarcinoma cellpatient responsepharmacologicpreclinical developmentrelapse patientsresearch studyresistance mechanismresponsetargeted treatmenttherapy resistanttumortumor microenvironmenttumorigenic
中文摘要
项目概要/摘要
胰腺癌是美国癌症死亡的第三大原因,对有效治疗的需求是非常迫切的。
可怕。KRAS在约95%的胰腺导管腺癌(PDAC)中突变激活,这是胰腺癌的主要病理特征。
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靶向疗法的发展确定为四种疗法之一,
外地的主要优先事项。Sotorasib最近被FDA批准为第一种直接KRAS抑制剂,用于
KRASG 12 C突变型肺癌。然而,sotorasib和所有其他临床候选药物在PDAC中的临床效用
有两个主要原因。首先,sotorasib靶向KRASG 12 C,这是一种代表不到2%的
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研究阶段。
发展其次,最初对KRASG 12 C抑制剂有反应的患者很快都会复发。早期研究
开始确定驱动抗性的遗传事件,并确定了RAS信号传导的预期成分,
患者然而,在大约一半的复发患者中没有明确的机制。完整的描述
这些机制将需要开发有效的组合,可以延长患者的反应,
KRAS靶向治疗。该建议建立在理解KRAS驱动程序的新兴概念基础上
机制,不同的突变对KRAS功能造成不同的后果。因此,
突变特异性驱动功能,可用于开发突变选择性组合疗法。
这些研究集中在PDAC中两个较少研究的非典型KRAS突变-KRASG 12 R,这是出乎意料的。
KRASQ 61 H,这是出乎意料的罕见。拟议的研究将利用直接药理学
PDAC中的KRASG 12 R和KRASQ 61 H抑制剂。CRISPR/Cas9全系统无偏遗传功能丧失
致癌信号通路文库将用于鉴定KRAS的治疗耐药机制
抑制作用初步数据强烈暗示已知和新的耐药机制。最后因为
KRASG 12 R和KRASQ 61 H突变型胰腺癌表现出明显的功能差异,这些研究将
可能会发现共同和不同的耐药机制KRAS抑制,这将导致不同的
KRAS抑制剂组合方法。该提案还描述了KrasG 12 R和KrasQ 61 H的开发
同源原位胰腺癌小鼠模型。这些新模型将被用来定义突变-
特定的癌症功能,并能够评估肿瘤微环境对肿瘤细胞的影响。
KRAS抑制单独和组合的后果。该提案的总体目标是进一步
阐明两种非典型KRAS突变如何驱动PDAC生长,并为识别
可以增加PDAC中突变特异性抗KRAS策略的临床有效性。
英文摘要
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.
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