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Defining oncogenic capacities of PAK7 mutations in human cancer

定义人类癌症中 PAK7 突变的致癌能力

基本信息

批准号：
8879404
负责人：
STEEN HENNING HANSEN
金额：
$ 23.03万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-09 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879404
关键词：
Address Advanced Malignant Neoplasm Affect Apical Apoptosis Architecture Attention Automobile Driving BRAF gene Biological Assay Caco-2 Cells Cadherins Cancer Patient Cancer cell line Carcinoma Cell Line Cell Polarity Cell Proliferation Cell-Cell Adhesion Cells Colon Carcinoma Colorectal Cancer Controlled Study Data Epithelial Epithelial Cells Family Gastric Adenocarcinoma Genes Genome Human MEL Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Missense Mutation Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nude Mice Oncogenes Oncogenic Phosphotransferases Probability Property Protein Kinase Relative (related person)Resistance Role STK11 gene Sequence Analysis Staging Technology Testing Therapeutic Tumor Suppressor Proteins Tumorigenicity Work Zinc Fingers anaplastic lymphoma kinase cancer cell cancer genome gastrointestinal carcinoma genome editing genome sequencing improved inhibitor/antagonist insertion/deletion mutation lung Carcinoma matrigel melanoma nuclease oncology p21 activated kinase preclinical study public health relevance research study targeted treatment therapeutic target trait tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Genome sequencing efforts have identified PAK7 (p21-activated kinase 7) as a potentially important cancer kinase. PAK7 ranked 17 among all 518 kinases in probability of harboring driver mutations for human cancer. The vast majority of PAK7 mutations in human cancer are missense and thus suggestive of a role as an oncogene. PAK7 mutations occur in a significant proportion of lung and gastrointestinal carcinomas, as well as in malignant melanomas. Our preliminary data suggest that cancer mutations in PAK7 potently stimulate kinase activity. However, PAK7 is a minimally characterized kinase, thus providing merit to address the following aims: (1) Are putative PAK7 driver mutations required for oncogenic capacities in cancer cells? (2) Are putative PAK7 driver mutations sufficient to promote epithelial oncogenesis? We will rigorously address these aims by genome editing to avoid confounding effects associated with exogenous expression or knockdown of genes. First, we will correct PAK7 missense mutations in human cancer cell lines. We will then determine whether correction of these mutations reverts any transformed capacities that these cell lines possess. Specifically, we will assay cell proliferation, apoptosis, invasion, and tumorigenicity in athymic mice. Second, we will introduce putative PAK7 driver mutations into the relatively well-differentiated colonic Caco-2 cells and bronchial 16HBE14o- cells. In addition to the capacities listed above, we will determine effects of PAK7 cancer mutations on parameters of normal epithelial architecture; a hallmark of differentiated epithelial cells with established tumor suppressor capacities. Specifically, we will test whether naturally occurring PAK7 mutations in cancer affect epithelial cell polarity, cell-cell adhesion, and lumen formation in 3D culture. Collectively, the proposed studies will provide a stringent initial approach to define the oncogenic potential of PAK7 mutations in human cancer and elucidate whether PAK7 represents a promising candidate in expanding targets for cancer therapeutics.