Mechanisms of PIK3CA helical domain mutations driving colorectal tumorigenesis

PIK3CA螺旋结构域突变驱动结直肠肿瘤发生的机制

基本信息

批准号：
10301099
负责人：
Zhenghe Wang
金额：
$ 40.09万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10301099
关键词：
1-Phosphatidylinositol 3-Kinase ATAC-seq Automobile Driving Breast Cancer Patient Cancer Etiology Cancer Science Catalytic Domain Cell Line Cell Nucleus Cells Cessation of life Clinical Trials Colonic Neoplasms Colorectal Colorectal Cancer Disease Drug Combinations EZH2 gene Engineering Enzymes FDA approved Foundations Fulvestrant Future Genes Genetically Engineered Mouse Goals Growth Histones Hot Spot Human IRS1 gene Immunocompetent Knock-in Malignant Neoplasms Modeling Mutate Mutation Nuclear Nuclear Translocation Oncogenes Oncogenic PIK3CA gene Pathway interactions Patients Phosphotransferases Pre-Clinical Model Precision therapeutics Proteins Proto-Oncogene Proteins c-akt Recurrence Role Signal Transduction Solid Specimen Testing Tumor-infiltrating immune cells United States alpelisib cancer cell colon cancer patients colon tumorigenesis colorectal cancer treatment effective therapy inhibitor/antagonist innovation knock-down mutant novel novel strategies novel therapeutics overexpression patient derived xenograft model personalized approach protein complex single-cell RNA sequencing tumor tumor growth tumor heterogeneity tumor xenograft tumor-immune system interactions

项目摘要

The overarching goal of this proposal is to develop precision therapy for PIK3CA-mutant colorectal cancer (CRC). Phosphatidylinositol 3-kinases (PI3K) are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. The PI of this application co-discovered that PIK3CA, which encodes p110α, is frequently mutated in a variety of human cancers, including ~30% of CRC. Most PIK3CA/p110α oncogenic mutations occur at two hot spot regions, one in the helical domain and the other in the kinase domain. Nearly half of all p110α mutations are located in the helical domain. Increasing evidence suggests that the helical domain and kinase mutations exert their oncogenic function through distinct mechanisms. For the helical domain mutations, we discovered that the oncogenic signal is transduced by two unique pathways. We previously found that the p110α helical domain mutant protein directly associates with IRS1 independent of p85 to activate PI3Kα-AKT. Now, our preliminary studies demonstrate that p85β disassociates from the p110α helical domain mutant protein complexes and translocates into the nucleus. The nuclear p85β stabilizes EZH1 and EZH2, two enzymes that catalyze histone H3K27 trimethylation. Remarkably, we found that a combination of EZH inhibitor GSK126 with a p110α-specific inhibitor Alpelisib induced tumor regression of CRCs harboring a PIK3CA helical domain mutation. Thus, we hypothesize that nuclear p85β promotes oncogenic functions of p110α helical domain mutations and that simultaneous inhibition of both nuclear p85β function and p110α kinase will be an effective approach to treat tumors with a helical domain mutation. Two aims are proposed to test the central hypothesis: 1) elucidate the mechanisms by which nuclear p85β promotes oncogenic functions of PIK3CA helical domain mutations; and 2) determine the efficacy of the combination of GSK126 and Alpelisib using a panel of CRC patient-derived xenografts with a PIK3CA helical domain mutation. Successful completion of our studies will demonstrate the combination of GSK126 and Alpelisib as an effective treatment for CRCs with PIK3CA helical domain mutations in preclinical models and lay a solid foundation for future clinical trials. Moreover, our studies uncover p85β nuclear translocation as a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic functions.

该提案的总体目标是开发针对 PIK3CA 突变结直肠癌的精准疗法 (CRC) 磷脂酰肌醇 3-激酶 (PI3K) 是由 p110 催化亚基和 p85 组成的异二聚体。本申请的 PI 共同发现编码 p110α 的 PIK3CA 经常出现。在多种人类癌症中发生突变，包括约 30% 的 CRC。大多数 PIK3CA/p110α 致癌突变发生。位于两个热点区域，一个位于螺旋结构域，另一个位于激酶结构域，几乎占所有 p110α 的一半。越来越多的证据表明螺旋结构域和激酶存在突变。突变通过不同的机制发挥其致癌功能。发现致癌信号是通过两种独特的途径转导的我们之前发现 p110α。螺旋结构域突变蛋白不依赖于 p85 直接与 IRS1 结合来激活 PI3Kα-AKT。初步研究表明 p85β 与 p110α 螺旋结构域突变蛋白分离核 p85β 复合并易位到细胞核中，稳定 EZH1 和 EZH2 这两种酶。值得注意的是，我们发现 EZH 抑制剂 GSK126 与 GSK126 的组合可以催化组蛋白 H3K27 三甲基化。 p110α 特异性抑制剂 Alpelisib 诱导含有 PIK3CA 螺旋结构域的 CRC 肿瘤消退因此，我们研究核 p85β 促进 p110α 螺旋结构域的致癌功能。突变，同时抑制核 p85β 功能和 p110α 激酶将是一种有效的方法提出了两个目标来检验中心假设： 1）阐明核p85β促进PIK3CA螺旋结构域致癌功能的机制突变；2) 使用一组 CRC 确定 GSK126 和 Alpelisib 组合的功效具有 PIK3CA 螺旋结构域突变的患者来源的异种移植物将成功完成我们的研究。证明 GSK126 和 Alpelisib 的组合可以有效治疗 PIK3CA 螺旋状结直肠癌此外，我们的研究还为临床前模型中的域突变奠定了坚实的基础。揭示 p85β 核转位作为 PIK3CA 螺旋结构域突变发挥其作用的新机制致癌功能。