Inhibiting oncogenic KRAS for cancer therapy

抑制致癌 KRAS 用于癌症治疗

• 批准号: 8637741
• 负责人: GARTH POWIS
• 金额: $ 38.03万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637741
• 关键词: Amino Acid Substitution; Automobile Driving; Binding; CNKSR1 gene; Cancer Cell Growth; Cancer Patient; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical Trials; Codon Nucleotides; Computer Simulation; Custom; Data; Diagnosis; Drug Targeting; Grant; Human; Individual; KRAS2 gene; Knowledge; Lead; Libraries; Malignant Neoplasms; Microscopy; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Proteins; Proteomics; Regulation; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Techniques; Transducers; Work; X-Ray Crystallography; base; cancer therapy; cell growth; cellular engineering; effective therapy; improved; inhibitor/antagonist; mutant; novel; novel therapeutic intervention; oncogene addiction; response; small molecule; therapy development; therapy resistant; tumor

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.

描述（由申请人提供）：RAS 癌基因是迄今为止已确定的最难以捉摸的癌症治疗靶点。突变型 KRAS (mut-KRAS) 是 RAS 的主要致癌形式，存在于 17-25% 的人类癌症中，在推动癌细胞生长和对治疗的耐药性中发挥着关键作用，在推动癌细胞生长和对治疗的耐药性中发挥着关键作用。它的作用如此强大，以至于超越了当今用于癌症治疗的许多新型分子靶向信号传导剂的有益作用。尽管在过去二十年中进行了多次尝试，但仍然没有针对 mut-KRAS 的有效疗法。 KRAS 突变仅限于少数位点，主要是密码子 12 和 13，其中不同的碱基颠换和转变导致不同的氨基酸取代，这些取代在不同的肿瘤类型中有所不同。了解不同形式的 mut-KRAS 激活的信号传导机制并寻找抑制 mut-KRAS 信号传导的药物可以说是当今癌症治疗中最重要的未满足需求。新发现提供了开发选择性抑制 mut-KRAS 疗法的潜力。这些研究所依据的假设是：“不同形式的 mut-KRAS 激活调节癌细胞生长和存活的不同下游信号传导途径，导致患者对治疗的反应不同。了解哪些途径被激活将允许不同形式的 mut-KRAS 选择性抑制信号传导”。 mut-KRAS 改善了 mut-KRAS 肿瘤的治疗。我们提出的新证据表明，用小分子靶向 mut-KRAS 信号纳米簇的蛋白质可以选择性抑制 mut-KRAS，但不会抑制 wt-KRAS 信号和细胞生长。了解这些纳米簇蛋白如何调节 mut-和 wt-KRAS 活性将为选择性抑制 mut-KRAS 的新治疗方法提供机会之窗。” 我们开发的探针可与 RAS 纳米簇结合，选择性抑制 mut-KRAS，但不抑制 wt-KRAS 信号传导和细胞生长。具体目标是； 1) 研究不同的mut-KRAS氨基酸取代激活多个KRAS下游信号通路中的哪一个以及激活的结构基础； 2) 研究哪些信号通路对于mut-KRAS癌基因成瘾和/或耐药至关重要 接受治疗； 3) 研究RAS纳米簇对mut-KRAS信号传导的调节以及选择性抑制mut-KRAS而非wt-KRAS细胞增殖的小分子纳米簇抑制剂的机制。