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Genetic dissection of oncogenic Kras signaling

致癌 Kras 信号传导的基因剖析

基本信息

批准号：
10656203
负责人：
Monte Meier Winslow
金额：
$ 42.82万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656203
关键词：
Alleles Area Bar Codes Biochemical Biology CRISPR/Cas technology Cancer Model Cancer Patient Cell Culture Techniques Cell Line Cessation of life Chemicals Clinical Clinical Trials Codon Nucleotides Consumption Correlative Study Data Dedications Dissection Environment Epithelial Cells Generations Genetic Genetically Engineered Mouse Genome engineering Genomics Genotype Goals Growth Histologic Human Impairment KRAS oncogenesis KRAS2 gene Lung Lung Neoplasms MEKs Malignant Neoplasms Malignant neoplasm of lung Maps Methods Modeling Molecular Mus Mutate Mutation Oncogenes Oncogenic PIK3CG gene PTPN11 gene Pathway interactions Patients Pharmacogenomics Physiological Positioning Attribute Proteins Research Research Personnel Signal Pathway Signal Transduction Somatic Cell System Therapeutic Therapeutic Uses Time Variant cancer care cancer genetics cancer genome cancer therapy cancer type carcinogenesis cost drug sensitivity experimental study gain of function genetic approach genome sequencing in vivo loss of function mathematical model mouse model mutant novel overexpression pharmacologic repaired tool tumor tumor growth tumorigenic

项目摘要

ABSTRACT Lung cancer is a prevalent cancer type that leads to more deaths than the next four major cancer types combined. KRAS is one of the most frequent oncogenes in human lung cancer. Despite more than 30 years of biochemical and cell culture studies, as well as correlative studies on human tumors and clinical trials, therapeutic options for patients with oncogenic KRAS-driven tumors are just beginning to emerge. KRAS is often mutated at codons 12 and 13, but these mutations are diverse and these different mutant forms of KRAS have dramatically different biochemical features. By integrating conventional genetically-engineered mouse models and CRISPR/Cas9-based somatic genome engineering with quantitative genomics and mathematical modeling, we recently established CRISPR/Cas9-based approaches that enable the generation and quantitative analysis of multiple tumor genotypes in parallel in vivo. By employing homology directed repair in somatic cells, we induce a panel of oncogenic Kras variants, and uncovered an unexpectedly dramatic difference in oncogenic potential of different Kras variants in vivo. In addition to the diversity of different oncogenic KRAS variants, the compendium of important pathways downstream of oncogenic KRAS remains relatively poorly understood. The goals of this proposal are 1) to use genomic and pharmacological methods to generate a quantitative understanding of different signaling requirements in cancers driven by different Kras variants and 2) to uncover novel functional regulators of Kras-driven carcinogenesis. To understand the basis for the differential oncogenic potential of different oncogenic Kras variants, we will use our multiplexed genetic approaches to quantify the impact of increasing either overall Kras signaling or discrete downstream pathways on the in vivo tumorigenic potential of diverse oncogenic Kras variants. We will also use therapeutic treatments to uncover the requirement for sustained PI3K and Raf/Mek/Erk signaling in established lung tumors driven by diverse Kras variants. Finally, to expand our understanding of Kras-driven tumorigenesis beyond the canonical effect pathways, we will directly analyze the function of novel Kras-interacting proteins on lung tumor growth in vivo. By performing multiplexed genomic and pharmacologic analyses of oncogenic Kras signaling in cancer, we will uncover the molecular mechanisms that contribute to tumor growth driven by different variants of KRAS. We will define specific therapeutic sensitivities of lung tumors driven by diverse oncogenic mutations. Our proposed research is significant because it will uncover interesting new areas of biology, motivate genotype-directed clinical trials, and facilitate precision cancer therapy for lung cancer patients with KRAS- mutant tumors.

摘要肺癌是一种普遍的癌症类型，导致的死亡人数超过了接下来的四种主要癌症类型加起来KRAS是肺癌中最常见的癌基因之一。尽管30多年来生物化学和细胞培养研究，以及人类肿瘤和临床试验的相关研究，对于具有致癌KRAS驱动的肿瘤的患者的治疗选择刚刚开始出现。KRAS是通常在密码子12和13处突变，但这些突变是多样的，这些不同的KRAS突变形式有着截然不同的生化特征通过整合传统的基因工程小鼠模型和基于CRISPR/Cas9的体细胞基因组工程，通过建模，我们最近建立了基于CRISPR/Cas9的方法，在体内平行定量分析多种肿瘤基因型。通过采用同源定向修复，在体细胞中，我们诱导了一组致癌的Kras变体，并发现了一个出乎意料的戏剧性的不同Kras变体在体内的致癌潜力的差异。除了不同的多样性致癌KRAS变体，致癌KRAS下游重要途径的概要仍然存在相对来说，了解得很少。该提案的目标是：1）使用基因组学和药理学方法，对不同Kras驱动的癌症中不同信号传导需求产生定量理解变体和2）发现Kras驱动的致癌作用的新功能调节剂。为了理解对于不同致癌Kras变异体的差异致癌潜力，我们将使用我们的多重遗传学方法，量化增加整体Kras信号传导或离散下游途径的影响的方法不同致癌Kras变异体的体内致瘤潜力。我们还将使用治疗性疗法为了揭示在已建立的肺肿瘤中持续的PI 3 K和Raf/Mek/Erk信号传导的需要，不同的Kras变体。最后，为了扩展我们对Kras驱动的肿瘤发生的理解，影响途径，我们将直接分析新的Kras相互作用蛋白对肺肿瘤生长的功能， vivo.通过对癌症中致癌Kras信号传导进行多重基因组和药理学分析，我们将揭示由不同的基因变体驱动的肿瘤生长的分子机制，克拉斯。我们将定义由不同致癌突变驱动的肺肿瘤的特定治疗敏感性。我们提出的研究是重要的，因为它将揭示有趣的新领域的生物学，激励基因型导向的临床试验，并促进KRAS肺癌患者的精确癌症治疗- 突变肿瘤