Defining RAS isoform- and mutation-specific roles in oncogenesis

描述（由申请人提供）：RAS癌基因（HRAS、KRAS和NRAS）是癌症中最常突变的癌基因家族。尽管经过三十多年的努力，目前还没有有效的RAS靶向治疗进入临床。导致这种失败的原因是药物开发中的失误和错误，这是由于该领域低估了RAS的复杂性。虽然最近的癌症基因组测序研究为特定癌症提供了更全面的遗传画像，但他们也证实了RAS突变是癌症的主要驱动因素，这些癌症包括美国癌症死亡的四个主要原因中的三个（肺癌，结直肠癌和胰腺癌）。一个“RAS复兴”现在已经开始，重新强烈的兴趣和努力，以确定和开发新的药理学策略，以靶向异常RAS功能的癌症治疗。我们开展该项目的理由是基于我们的信念，即关于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药物发现方法至关重要。我们的总体前提是，RAS突变并非生来平等。我们的总体假设是RAS亚型和RAS突变之间存在显著差异，并且这些在不同癌症中具有不同的致癌后果。四个项目组成了我们的P01，每个项目都由一位长期的RAS研究人员领导，他为一个旨在利用我们的优势并最大限度地减少我们的弱点的强大项目间合作的计划带来了互补和独特的实验专业知识。总的来说，我们将产生一个有凝聚力的和全面的研究，这是无法通过单独的实验室工作来实现的。我们的结构，生物化学和生物学的努力将确定RAS亚型和突变特异性扰动RAS功能。从长远来看，这些不同的扰动可能代表了可靶向的脆弱性，这将揭示开发用于癌症治疗的突变特异性抗RAS疗法的新方法。项目1侧重于胰腺癌中KRAS突变的细胞研究，与项目2中KRAS的结构和生化研究密切协调。NRAS的项目2研究得到了黑色素瘤中突变型NRAS和野生型RAS等位基因的项目3研究的补充。项目4将使用基因工程小鼠肺癌模型来解决癌症中KRAS优先突变的基础。核心A将提供财务监督、信息交流的行政协调以及对该机构间计划项目的生物统计支持。核心B将提供创新的蛋白质组学技术，用于RAS突变选择性效应信号的无偏分析。我们的项目发现将有助于重塑抗RAS药物的发现，目标是开发针对RAS突变特定子集的疗法。与公共卫生的相关性：RAS突变在美国癌症死亡的四大原因中的三个非常常见。开发有效的抗RAS治疗策略将显着减少癌症对生产力和人类生命的损失。

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.