Inhibiting oncogenic KRAS for cancer therapy

描述（由申请人提供）：RAS癌基因是目前发现的最难以捉摸的癌症治疗靶点。突变型KRAS （mutt -KRAS）是RAS的主要致癌形式，存在于17-25%的人类癌症中，在驱动癌细胞生长和对治疗的抵抗中起关键作用，在驱动癌细胞生长和对治疗的抵抗中起关键作用。它的作用是如此强大，以至于它超过了许多目前用于治疗癌症的新型分子靶向信号剂的有益作用。尽管在过去的二十年中进行了多次尝试，但仍然没有有效的治疗mutkras的方法。KRAS突变仅限于少数位点，主要是密码子12和13，不同的碱基翻转和转移导致不同的氨基酸取代，这在不同的肿瘤类型中有所不同。了解由不同形式的mut-KRAS激活的信号机制，并寻找抑制mut-KRAS信号的药物，可以说是当今癌症治疗中最重要的未满足的需求。新的发现为开发选择性抑制mut1 - kras的疗法提供了潜力。这些研究基于的假设是：“不同形式的muta - kras激活不同的下游信号通路，调节癌细胞的生长和存活，导致患者对治疗的反应不同。了解哪些途径被激活，将允许通过不同形式的选择性抑制信号

DESCRIPTION (provided by applicant): The RAS oncogene is the most elusive cancer therapy target yet identified. Mutant KRAS (mut-KRAS) is the predominant oncogenic form of RAS, and is present in 17-25% of all human cancers where it plays a critical role in driving cancer cell growth and resistance to therapy where it plays a critical role in driving cancer cell growth and resistance to therapy. Its effects are so powerful that it overrides the beneficial effects of many of the new molecularly targeted signaling agents in use for cancer today. Despite numerous attempts over the last two decades there is still no effective therapy for mut-KRAS. KRAS mutations are limited to a few sites, primarily codons 12 and 13, where different base transversions and transitions lead to different amino acid substitutions which vary in different tumor types. Understanding the signaling mechanisms activated by the different forms of mut-KRAS and finding agents to inhibit mut-KRAS signaling is arguably the most important unmet needs in cancer therapy today. New findings offer the potential of developing therapies that selectively inhibit mut-KRAS. The hypothesis upon which the studies are based is that: "Different forms of mut-KRAS activate different downstream signaling pathways regulating cancer cell growth and survival, leading to differences in patient response to therapy. Knowing which pathways are activated will allow selective inhibition of signaling by the different forms of mut-KRAS leading to improved therapy for mut-KRAS tumors. New evidence we present shows that targeting proteins of the mut-KRAS signaling nanocluster with small molecules can lead to selective inhibition of mut-KRAS but not wt-KRAS signaling and cell growth. Understanding how these nanocluster proteins work in regulating mut- and wt-KRAS activity will provide a window of opportunity for new therapeutic approaches for selective inhibition of mut-KRAS ". The overall objectives of our study are to gain a greater understanding of the structural and cellular mechanisms of signaling by different forms of mut-KRAS that could explain differences in patient response and resistance to therapy; and to investigate the mechanism of a new small molecule probe we have developed that binds to the RAS nanocluster to selectively inhibit mut-KRAS but not wt-KRAS signaling and cell growth. The Specific Aims are; 1) To investigate which of multiple KRAS downstream signaling pathways are activated by different mut-KRAS amino acid substitutions and the structural basis for the activation; 2) To investigate which signaling pathways are essential for mut-KRAS oncogene addiction and/or resistance to therapy; and 3) To investigate the regulation of mut-KRAS signaling by the RAS nanocluster and the mechanism of a small molecule nanocluster inhibitor that selectively inhibits mut-KRAS but not wt-KRAS cell proliferation.