Role of Erbb3 kinase activity in colorectal tumorigenesis.

Erbb3 激酶活性在结直肠肿瘤发生中的作用。

基本信息

批准号：
10329986
负责人：
Zhenghe Wang
金额：
$ 42.56万
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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10329986
关键词：
Antibody Therapy Biological Markers Cancer Etiology Cancer Model Carcinogens Cell Line Cells Cessation of life Clinical Trials Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer Data Disease Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family Family member Foundations Future Gene Expression Genes Genetically Engineered Mouse Goals Growth Human IRS1 gene Immune Immune checkpoint inhibitor Impairment Interferon Type II Interferons Knock-in Malignant Neoplasms Malignant neoplasm of lung Microsatellite Repeats Modeling Mus Mutant Strains Mice Mutate Mutation Neoplasm Metastasis Oncogenic PDL1 pathway PDPK1 gene Phosphorylation Phosphotransferases Play Protein-Serine-Threonine Kinases Receptor Protein-Tyrosine Kinases Resistance Role Serine Signal Pathway Signal Transduction Site Solid Testing Threonine Trastuzumab Tumorigenicity United States Xenograft procedure anti-PD1 antibodies anti-PD1 therapy cancer cell cancer therapy colon cancer cell line colon cancer patients colon tumorigenesis humanized mouse innovation kinase inhibitor malignant breast neoplasm member metastatic colorectal mimetics mouse model mutant new therapeutic target novel therapeutics overexpression patient derived xenograft model personalized approach predicting response programmed cell death ligand 1 response success therapeutic target transcription factor tumor tumor growth tumor microenvironment tumor progression tumor xenograft tumorigenesis

项目摘要

The overarching goals of this proposal are to determine if Erbb3 kinase plays a critical role in colorectal tumorigenesis and to test if colorectal cancer with oncogenic Erbb3 mutations respond better to anti-PD1 antibody. Erbb3, a member of the EGFR family of receptor protein tyrosine kinases, is mutated in a variety of human cancers including colorectal cancer (CRC). Unlike other EGFR family members, the kinase domain of Erbb3 is thought to be a pseudo-kinase without enzymatic activity. Although it is well documented that Erbb3 plays an oncogenic role in tumorigenesis, the mechanisms by which Erbb3 activation drives tumorigenesis are largely unknown. We made the paradigm-shifting discovery that the pseudo-kinase domain of Erbb3 is a serine/threonine (S/T) kinase activated by phosphorylation of a serine site in the juxatomembrane domain, and that its kinase activity is required for robust tumor growth in both xenograft and genetically engineered mouse models. Moreover, we found that a Erbb3 kinase-dead mutant impairs interferon-γ (IFN-γ)-induced PD-L1 expression in CRCs. Interestingly, knockin of an oncogenic Erbb3 mutation in mouse colon cancer cell lines renders them sensitive to anti-PD1 antibody therapy. Here we propose two aims to determine the role of Erbb3 S/T kinase in (1) colorectal tumorigenesis and (2) the response of colorectal cancers to immune checkpoint inhibitors. Successful completion of our proposed studies will lay a solid foundation for targeting Erbb3 mutant CRCs with Erbb3 kinase inhibitors and/or immune checkpoint inhibitors. Given that aberrant activation of Erbb3 causes resistance to various cancer therapies including Herceptin in breast cancer and EGFR inhibitors in lung cancer, the impact of our studies will have a broad impact on cancer therapy.