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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：
10549861
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/10549861
关键词：
Antibody Therapy 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 checkpoint inhibitor Impairment Interferon Type II Knock-in Malignant Neoplasms Malignant neoplasm of lung Microsatellite Instability Microsatellite Repeats Modeling Mus Mutant Strains Mice Mutate Mutation Neoplasm Metastasis Oncogenic PDL1 pathway PDPK1 gene PIK3CG 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 biomarker identification cancer cell cancer therapy colon cancer cell line colon cancer patients colon tumorigenesis humanized mouse immunomodulatory therapies 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.

这项提议的首要目标是确定erbB3激酶是否在结直肠疾病中起关键作用。肿瘤的发生和检测具有致癌的erbB3突变的结直肠癌对抗PD1的反应是否更好抗体。ErbB3是受体蛋白酪氨酸激酶EGFR家族的成员，在多种人类癌症，包括结直肠癌(CRC)。与其他EGFR家族成员不同的是， ErbB3被认为是一种没有酶活性的假激酶。尽管有很好的证据表明，erbB3 在肿瘤发生中起致癌作用，erbB3激活驱动肿瘤发生的机制是很大程度上是未知的。我们做出了一个范式转换的发现，即erbB3的假激酶域是一个丝氨酸/苏氨酸激酶(S/T)通过膜旁结构域中一个丝氨酸位点的磷酸化而激活，以及它的激酶活性是异种移植和基因工程小鼠肿瘤生长所必需的模特们。此外，我们还发现，一个erbB3激酶死亡的突变体会削弱干扰素-γ(干扰素-γ)诱导的PD-L1 在CRC中的表达。有趣的是，小鼠结肠癌细胞系中致癌的erbB3突变的敲击使他们对抗PD1抗体治疗敏感。在这里，我们提出了两个目标来确定erbB3的作用 S/T激酶在(1)结直肠癌发生和(2)结直肠癌免疫检查点应答中的作用抑制剂。我们建议的研究的成功完成将为靶向erbB3突变奠定坚实的基础使用erbB3激酶抑制剂和/或免疫检查点抑制剂的CRC。鉴于erbB3的异常激活引起对多种癌症治疗的抵抗，包括乳腺癌的赫赛汀和肺癌的EGFR抑制剂癌症，我们的研究将对癌症的治疗产生广泛的影响。