A protein-complex as a novel therapeutic target for K-Ras dependent colon cancer

蛋白质复合物作为 K-Ras 依赖性结肠癌的新型治疗靶点

• 批准号: 9275435
• 负责人: GUAN CHEN
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275435
• 关键词: Binding; Cancer Etiology; Cessation of life; Client; Clinical; Colon Carcinoma; Complex; Development; Event; Growth; Healthcare; Heat-Shock Proteins 90; In Vitro; KRAS2 gene; Malignant - descriptor; Malignant Neoplasms; Mitogen-Activated Protein Kinases; Molecular Chaperones; Mus; Mutate; Oncoproteins; Pharmacology; Phosphorylation; Phosphotransferases; Pirfenidone; Play; Proteins; Reporting; Role; Signal Transduction; Small Interfering RNA; Specimen; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; United States; Veterans; Xenograft procedure; cancer cell; clinically significant; in vivo; inhibitor/antagonist; malignant phenotype; multicatalytic endopeptidase complex; new therapeutic target; novel strategies; novel therapeutics; outcome forecast; protein complex; protein expression; public health relevance; ras Proteins; small hairpin RNA; targeted treatment; therapeutic development; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Malignant phenotypes are driven by a group of coordinated proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is especially true for Ras- dependent cancers, as the Ras oncoprotein is non-druggable and targeting its interaction with key partner proteins may be essential for therapeutic development. K-Ras is mutated in up to 50% of colon cancers, and has been implicated in malignant development and progression. There is thus an urgent need to develop targeted therapies for K-Ras mutated (MT-K-Ras) colon cancer. This proposal will test the hypothesis that a p38g-activated ternary complex with MT-K-Ras and heat shock protein 90 (Hsp90) is a novel therapeutic target for K-Ras dependent colon cancer. This hypothesis is supported by our preliminary studies showing that p38g mitogen-activated protein kinase (MAPK), an established Ras effector, binds Hsp90, a chaperone, and MT-K-Ras, but not wild-type (WT) K-Ras, in colon cancer cells. Moreover, p38g phosphorylates Hsp90, and pharmacological inhibitors of p38g or Hsp90 disrupt the ternary complex, decrease MT-K-Ras levels of protein expression, and selectively inhibit K-Ras dependent growth in vitro and/or in vivo. Together, these results indicate that the p38g activated ternary complex with Hsp90 and MT-K-Ras is a potential therapeutic target for K-Ras dependent colon cancer. The following specific aims will test this hypothesis: 1) To demonstrate that p38g and Hsp90 form a ternary protein complex that protects MT-K-Ras from proteasome- dependent degradation; 2) To demonstrate if p38g activates Hsp90 by inducing its phosphorylation at S595 and whether this event is central to the formation of the MT-K-Ras/p38g/Hsp90 complex; and 3) To demonstrate the therapeutic potential and clinical significance of the p38g/Hsp90/K-Ras complex in colon cancer. These studies will demonstrate that the p38g-activated ternary-complex is a novel therapeutic target for MT-K-Ras colon cancer. Disruption of this complex with pharmacological inhibitors of p38g and Hsp90 is a highly promising therapeutic strategy for the treatment of K-Ras dependent colon cancer. Since colon cancer is the second leading cause of cancer-related death in the United States, discovery of novel targeted therapeutics for K-Ras dependent colon cancer will directly contribute to veteran's health care.

描述（由申请人提供）： 恶性表型是由一组协调蛋白驱动的，针对一组功能上相互依赖的分子应该更有效地进行治疗干预。对于 Ras 依赖性癌症尤其如此，因为 Ras 癌蛋白是非药物性的，并且靶向其与关键伙伴蛋白的相互作用可能对于治疗开发至关重要。 K-Ras 在高达 50% 的结肠癌中发生突变，并且与恶性发生和进展有关。因此，迫切需要开发针对 K-Ras 突变（MT-K-Ras）结肠癌的靶向疗法。该提案将检验以下假设：p38g 激活的三元复合物与 MT-K-Ras 和热休克蛋白 90 (Hsp90) 是 K-Ras 依赖性结肠癌的新型治疗靶点。我们的初步研究支持了这一假设，该研究表明 p38g 丝裂原激活蛋白激酶 (MAPK)（一种已确定的 Ras 效应子）在结肠癌细胞中与 Hsp90（一种分子伴侣）和 MT-K-Ras 结合，但不与野生型 (WT) K-Ras 结合。此外，p38g 磷酸化 Hsp90，p38g 或 Hsp90 的药理学抑制剂会破坏三元复合物，降低蛋白表达的 MT-K-Ras 水平，并在体外和/或体内选择性抑制 K-Ras 依赖性生长。总之，这些结果表明 p38g 激活的 Hsp90 和 MT-K-Ras 三元复合物是 K-Ras 依赖性结肠癌的潜在治疗靶点。以下具体目标将检验这一假设： 1) 证明 p38g 和 Hsp90 形成三元蛋白复合物，保护 MT-K-Ras 免受蛋白酶体依赖性降解； 2) 证明p38g是否通过诱导其S595磷酸化来激活Hsp90，以及该事件是否对于MT-K-Ras/p38g/Hsp90复合物的形成至关重要； 3) 证明p38g/Hsp90/K-Ras复合物在结肠癌中的治疗潜力和临床意义。这些研究将证明 p38g 激活的三元复合物是 MT-K-Ras 结肠癌的新型治疗靶点。用 p38g 和 Hsp90 的药理学抑制剂破坏这种复合物是治疗 K-Ras 依赖性结肠癌的一种非常有前途的治疗策略。由于结肠癌是美国癌症相关死亡的第二大原因，因此发现 K-Ras 依赖性结肠癌的新型靶向疗法将直接有助于退伍军人的医疗保健。