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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：RAS Oncogenes（HRAS，KRAS和NRA）构成了癌症中最常见的癌基因家族。尽管经过三十多年的强化努力，目前尚无有效的RAS靶向疗法到达诊所。导致这种失败的原因是由于该领域低估了RAS的复杂性，因此在药物开发中犯了错过和错误。尽管最近的癌症基因组测序研究为特定癌症提供了更全面的遗传肖像，但他们还证实了RAS突变是癌症的主要驱动因素，在美国（肺，有色和胰腺癌）癌症死亡的四个主要原因中，有三个主要原因中的三个。现在已经开始了“ RAS文艺复兴”，并重新兴趣和努力识别和制定新的药物策略，以靶向异常的RAS功能进行癌症治疗。我们对该计划项目的理由是基于我们的信念，即有关RAS功能的关键问题尚待解决，并且他们的解决方案对于促进对抗RAS药物发现的知识渊博和有效的方法至关重要。我们的总体前提是，RAS突变不是平等的。我们的总体假设是RAS同工型和RAS突变之间存在显着差异，并且这些差异在不同的取消中具有明显的致癌后果。四个项目综合我们的P01，每个项目由一位长期存在的RAS研究人员领导，他们将完整而独特的实验专业知识带入了一个计划，该计划旨在旨在强大的项目间合作，以利用我们的优势并最大程度地减少我们的弱点。总的来说，我们将进行一项具有凝聚力和全面的研究，该研究无法由自己工作的个别实验室实现。我们的结构，生化和生物学努力将确定RAS同工型和突变特异性对RAS功能的扰动。从长远来看，这些独特的扰动可能代表可靶向的漏洞，这些漏洞将揭示开发突变特异性抗RAS治疗癌症治疗的新方法。项目1侧重于胰腺癌中KRAS突变的细胞研究，与项目2中的KRAS的结构和生化研究密切协调。NRAS的项目2研究是由黑色素瘤突变NRA和野生型RAS等位基因的项目3研究完成的。项目4将使用一般设计的肺癌小鼠模型来解决癌症中KRAS首选突变的基础。核心A将提供财务监督，信息交换的行政协调以及该机构间计划项目的生物统计学支持。核心B将提供创新的蛋白质组学技术，用于RAS突变选择性效应子信号传导的无偏分析。我们的计划发现将有助于重塑抗RAS药物发现，目的是开发针对RAS突变的特定子集的疗法。与公共卫生相关：在美国癌症死亡的前四个原因中，有三个原因很常见。制定有效的抗RAS治疗策略将显着降低生产力和人类生命的损失。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
通讯作者：

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