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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：
10463781
负责人：
Zhenghe Wang
金额：
$ 39.29万
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/10463781
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 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突变型结直肠癌的精确治疗方法