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PIK3CA突变结肠癌的精确疗法（CRC）。磷脂酰肌醇3-激酶（PI3K）是由P110催化亚基和P85组成的异二聚体监管亚基。该应用程序的PI共同发现，编码p110α的Pik3Ca经常是在各种癌症中突变，包括约30％的CRC。大多数PIK3CA/P110α致癌突变发生在两个热点区域，一个在螺旋域，另一个在激酶结构域中。所有P110α的几乎一半突变位于螺旋域中。越来越多的证据表明螺旋结构域和激酶突变通过不同的机制发挥其致癌功能。对于螺旋结构域突变，我们发现致癌信号由两个独特的途径翻译。我们以前发现P110α 螺旋结构域突变蛋白与p85无关的IRS1直接关联以激活PI3Kα-AKT。现在，我们的初步研究表明，p85β与p110α螺旋结构域突变蛋白的分离复合物并易位到核。核p85β稳定EZH1和EZH2，这是两个酶，催化组蛋白H3K27三甲基化。值得注意的是，我们发现EZH抑制剂GSK126与 P110α特异性抑制剂alpelisib诱导具有PIK3CA螺旋结构域的CRC的肿瘤回归突变。这，我们假设核p85β促进了p110α螺旋结构域的致癌功能突变以及对核p85β功能和p110α激酶的简单抑制作用将是有效的用螺旋结构域突变治疗肿瘤的方法。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）确定使用一组CRC的GSK126和Alpelisib组合的效率具有PIK3CA螺旋结构域突变的患者衍生的Xenographictics。成功完成学习将演示GSK126和Alpelisib作为PIK3CA Helical的有效治疗方法的组合临床前模型中的域突变，并为将来的临床试验奠定了坚实的基础。而且，我们的研究发现p85β核转运是一种新机制致癌功能。