Defining RAS isoform- and mutation-specific roles in oncogenesis

DESCRIPTION（由申请人提供）：RAS癌基因（HRAS， KRAS和NRAS）是癌症中最常见的突变癌基因家族。尽管经过三十多年的努力，目前还没有有效的ras靶向治疗方法进入临床。导致这一失败的原因是药物开发中的失误和错误，导致该领域低估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基因图谱，但它们也证实了RAS突变是癌症的主要驱动因素，在美国，癌症死亡的四大原因中，有三种是RAS突变（肺癌、结直肠癌和胰腺癌）。“RAS复兴”现在已经开始，人们对识别和开发针对异常RAS功能的新药理学策略重新产生了浓厚的兴趣和努力，以用于癌症治疗。我们开展该项目的理由是基于我们的信念，即RAS功能的关键问题仍有待解决，而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突变不是生来平等的。我们的首要假设是RAS亚型和RAS突变之间存在显著差异，并且这些在不同的癌症中具有不同的致癌后果。我们的P01由四个项目组成，每个项目都由一位资深的RAS研究员领导，他为项目间的合作带来了互补和独特的实验专业知识，从而充分利用我们的优势，最大限度地减少我们的弱点。总的来说，我们将产生一个有凝聚力和全面的研究，这是单个实验室自己工作无法实现的。我们在结构、生化和生物学方面的努力将确定RAS异构体和突变特异性对RAS功能的扰动。从长远来看，这些不同的扰动可能代表可靶向的脆弱性，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配合。项目2的NRAS研究由项目3的突变型NRAS和野生型RAS等位基因在黑色素瘤中的研究补充。项目4将使用基因工程小鼠肺癌模型来解决KRAS在癌症中的优先突变的基础。核心A将在该机构间项目中提供财务监督、信息交换行政协调和生物统计支持。Core B将提供创新的蛋白质组学技术，对RAS突变选择效应信号进行无偏分析。我们的项目发现将有助于重塑抗RAS药物的发现，目标是开发针对特定RAS突变亚群的治疗方法。与公共卫生的相关性：在美国癌症死亡的四大原因中，RAS突变在其中三种中非常常见。有效的抗ras治疗策略的发展将显著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.