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RAS癌基因(HRAS、KRAS和NRAS)是人类最常发生突变的癌基因家族 癌症。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 已经到达诊所。造成这一失败的原因是药物方面的失误和错误 由于实地低估了RAS的复杂性，导致了发展。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画像，他们还 证实RAS突变是癌症的主要驱动因素，包括四个主要原因中的三个 美国的癌症死亡人数(肺癌、结直肠癌和胰腺癌)。“RAS文艺复兴”现在已经开始， 重新燃起了强烈的兴趣和努力，以确定和开发针对异常的新药物策略 RAS在癌症治疗中的作用。我们支持该计划项目的理由是我们相信Key 关于RAS职能的问题仍有待解决，这些问题的解决将对促进更多 抗RAS药物发现的知识和有效方法。我们的总体前提是RAS 突变并不是平等的。我们最重要的假设是， RAS异构体和RAS突变，这些在不同的癌症中有不同的致癌后果。 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，他带来了补充和 为计划提供独特的实验专业知识，旨在加强项目间协作，充分利用我们的 我们的长处和短处被最小化。总体而言，我们将产生一个连贯和全面的研究 这不可能由单独的实验室独立工作来实现。我们的结构、生化和 生物学工作将确定RAS异构体和突变对RAS功能的特异性扰动。在漫长的岁月里 术语，这些不同的扰动可能代表有针对性的漏洞，这些漏洞将揭示新的方法 开发针对突变的抗RAS疗法用于癌症治疗。项目1的重点是细胞研究 胰腺癌中KRAS突变与KRAS结构和生化研究密切相关 在项目2中，项目2对NRAS的研究得到了项目3对突变体和野生型的研究的补充 黑色素瘤中的RAS等位基因。项目4将使用肺癌的基因工程小鼠模型来解决 KRAS基因在癌症中优先突变的基础。核心A将提供财务监督、行政管理 在这一机构间计划项目中协调信息交换和生物统计支持。 Core 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 效应器信号。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RAS突变特定亚群的治疗方法。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，有三种非常常见。高效抗RAS药物的研究进展 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。

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.