Defining RAS isoform- and mutation-specific roles in oncogenesis

定义 RAS 异构体和突变在肿瘤发生中的特异性作用

• 批准号: 9982047
• 负责人: CHANNING J. DER
• 金额: $ 160.94万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-22 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982047
• 关键词: Address; Administrative Coordination; Alleles; Antineoplastic Agents; Belief; Biochemical; Biological; Biometry; Cancer Etiology; Cessation of life; Clinic; Collaborations; Colorectal Cancer; Complement; Defect; Development; Failure; Family; Frequencies; Gene Family; Genetic; Genetically Engineered Mouse; Goals; Growth; Human; Individual; KRAS2 gene; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Motivation; Mutate; Mutation; Oncogenes; Oncogenic; Oncoproteins; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phosphoproteins; Portraits; Property; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Public Health; RAS genes; Recording of previous events; Renaissance; Research; Research Personnel; Research Support; Resolution; Role; Signal Transduction; Structure; Technology; base; cancer cell; cancer genome; cancer survival; cancer therapy; clinical application; cohesion; design; drug development; drug discovery; experience; genome sequencing; innovation; innovative technologies; inter-institutional; interest; melanoma; mutant; novel strategies; premature; productivity loss; programs; protein function; ras Oncogene; research study; success; targeted treatment; therapy development; treatment strategy; tumorigenesis

DESCRIPTION (provided by applicant): The RAS oncogenes (HRAS, KRAS and NRAS) comprise the most frequently mutated oncogene family in cancer. Despite more than three decades of intensive effort, presently no effective RAS-targeted therapies have reached the clinic. Contributing to this failure have been missteps and mistakes made in drug development, resulting from the field underestimating the complexities of RAS. While recent cancer genome sequencing studies have provided a more comprehensive genetic portrait of specific cancers, they have also verified that RAS mutations are the major drivers of cancers that comprise three of the four major causes of cancer deaths in the US (lung, colorectal and pancreatic cancer). A "RAS Renaissance" has now begun, with renewed intense interest and effort to identify and develop new pharmacologic strategies to target aberrant RAS function for cancer treatment. Our rationale for this Program Project is based on our belief that key issues regarding RAS function remain to be resolved and that their resolution will be vital to facilitate more knowledgeable and effective approaches for anti-RAS drug discovery. Our overall premise is that RAS mutations are not created equal. Our overarching hypotheses are that there are significant differences among RAS isoforms and RAS mutations, and that these have distinct oncogenic consequences in different cancers. Four Projects comprise our P01, each led by a long-standing RAS researcher who brings complementary and distinct experimental expertise to a Program designed for strong inter-project collaborations that leverage our strengths and minimize our weaknesses. Collectively, we will produce a cohesive and comprehensive study that could not be achieved by individual laboratories working on their own. Our structural, biochemical and biological efforts will identify RAS isoform- and mutation-specific perturbations to RAS function. In the long term, these distinct perturbations may represent targetable vulnerabilities that will reveal new approaches to develop mutation-specific anti-RAS therapies for cancer treatment. Project 1 focuses on cellular studies of KRAS mutations in pancreatic cancer, closely coordinated with the structural and biochemical studies of KRAS in Project 2. Project 2 studies of NRAS are complemented by Project 3 studies of mutant NRAS and wild type RAS alleles in melanoma. Project 4 will use genetically engineered mouse models of lung cancer to address the basis for the preferential mutation of KRAS in cancer. Core A will provide financial oversight, administrative coordination of information exchange, and biostatistics support across this inter-institutional Program Project. Core B will provide innovative proteomics technologies for unbiased profiling of RAS mutation-selective effector signaling. Our Program findings will help to reshape anti-RAS drug discovery with the goal of developing therapies targeting specific subsets of RAS mutations. Relevance to Public Health: RAS mutations are very common in three of the top four causes of US cancer deaths. Development of effective anti-RAS treatment strategies will significantly reduce the loss of productivity and human lives to cancer.

描述(申请人提供)：RAS癌基因(HRAS、KRAS和NRAS)是癌症中最常见的突变癌基因家族。尽管经过了三十多年的密集努力，目前还没有有效的RAS靶向疗法进入临床。造成这一失败的原因是药物开发中的失误和错误，原因是该领域低估了RAS的复杂性。虽然最近的癌症基因组测序研究提供了特定癌症的更全面的基因画像，但他们也证实了RAS突变是癌症的主要驱动因素，这些癌症构成了美国四大癌症死亡原因中的三种(肺癌、结直肠癌和胰腺癌)。“RAS复兴”现在已经开始，人们重新产生了强烈的兴趣和努力，以确定和开发新的药理策略，以针对癌症治疗中异常的RAS功能。我们为该计划项目提供的理由是基于我们的信念，即有关RAS功能的关键问题仍有待解决，这些问题的解决对于促进更有知识和更有效的抗RAS药物开发方法至关重要。我们的总体前提是RAS突变并不是生来平等的。我们的主要假设是，RAS亚型和RAS突变之间存在显著差异，并且在不同的癌症中具有不同的致癌后果。四个项目组成了我们的P01，每个项目都由一名长期从事RAS研究的人员领导，他将补充和独特的实验专业知识带入一个旨在加强项目间协作的计划，以利用我们的优势并最大限度地减少我们的劣势。总体而言，我们将产生一项有凝聚力的全面研究，这是单独的实验室无法完成的。我们的结构、生化和生物学努力将确定RAS异构体和突变对RAS功能的特异性扰动。从长远来看，这些不同的干扰可能代表有针对性的脆弱性，这将揭示开发癌症治疗的突变特异性抗RAS疗法的新方法。项目1专注于胰腺癌中KRAS突变的细胞学研究，与项目2中KRAS的结构和生化研究密切相关。项目2的NRAS研究与项目3黑色素瘤中突变的NRAS和野生型RAS等位基因的研究相辅相成。项目4将使用肺癌的基因工程小鼠模型来解决癌症中KRAS优先突变的基础。核心A将在整个机构间计划项目中提供财务监督、信息交换的行政协调和生物统计支持。核心B将提供创新的蛋白质组学技术，以无偏见地分析RAS突变选择性效应信号。我们的计划发现将有助于重塑抗RAS药物发现，目标是开发针对特定RAS突变亚群的治疗方法。与公共卫生相关：RAS突变在美国癌症死亡的前四大原因中的三个中非常常见。开发有效的抗RAS治疗策略将大大减少因癌症而造成的生产力损失和生命损失。

项目成果

Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.

• DOI: 10.3389/fmolb.2021.707439
• 发表时间: 2021
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Osaka N;Hirota Y;Ito D;Ikeda Y;Kamata R;Fujii Y;Chirasani VR;Campbell SL;Takeuchi K;Senda T;Sasaki AT
• 通讯作者: Sasaki AT

An ultra-sensitive method to detect mutations in human RAS templates.

• DOI: 10.1080/21541248.2022.2083895
• 发表时间: 2022-01
• 期刊: Small GTPases

Distinct responses to rare codons in select Drosophila tissues.

• DOI: 10.7554/elife.76893
• 发表时间: 2022-05-06
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Allen, Scott R.;Stewart, Rebeccah K.;Rogers, Michael;Ruiz, Ivan Jimenez;Cohen, Erez;Laederach, Alain;Counter, Christopher M.;Sawyer, Jessica K.;Fox, Donald T.
• 通讯作者: Fox, Donald T.

Post-translational modification of RAS proteins.

• DOI: 10.1016/j.sbi.2021.06.015
• 发表时间: 2021-12
• 期刊: Current opinion in structural biology
• 影响因子: 6.8
• 作者: Campbell SL;Philips MR
• 通讯作者: Philips MR

Wild-type Kras expands and exhausts hematopoietic stem cells.

野生型 Kras 会扩增并耗尽造血干细胞。

• DOI: 10.1172/jci.insight.98197
• 发表时间: 2018
• 期刊: JCI insight
• 影响因子: 8
• 作者: Sasine,JoshuaP;Himburg,HeatherA;Termini,ChristinaM;Roos,Martina;Tran,Evelyn;Zhao,Liman;Kan,Jenny;Li,Michelle;Zhang,Yurun;deBarros,StéphanieC;Rao,DineshS;Counter,ChristopherM;Chute,JohnP
• 通讯作者: Chute,JohnP