P53 survival target DDR1 kinase in DNA damage response and carcinogenesis

P53 存活靶标 DDR1 激酶在 DNA 损伤反应和致癌作用中的作用

基本信息

批准号：
9017978
负责人：
SAM W LEE
金额：
$ 39.8万
依托单位：
MASSACHUSETTS GENERAL 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：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017978
关键词：
Apoptosis Biochemical Cancer cell line Cell Cycle Arrest Cell Death Cell Survival Chemicals Complex DDR1 gene DNA Damage DNA Sequence Alteration Data Development Drug resistance Epithelial Event Gefitinib Gene Expression Gene Targeting Genetic Genomic approach Genotoxic Stress Goals Health Human In Vitro Lung Lymphoma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of esophagus Malignant neoplasm of ovary Mammary Neoplasms Mediating Modeling Molecular Mouse Mammary Tumor Virus Mus Mutate Mutation Oncogenic Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Protein Tyrosine Kinase Protein p53 Recovery Reporting Resistance Role Structure TP53 gene Testing Therapeutic Translating Up-Regulation biological adaptation to stress cancer cell cancer genomics carcinogenesis cell transformation gain of function mutation genetic approach genotoxicity in vivo inhibitor/antagonist kinase inhibitor malignant breast neoplasm migration mutant novel receptor response tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The central coordinator of the genotoxic/DNA damage stress response is tumor suppressor p53, which regulates the expression of genes involved in cell cycle arrest and apoptosis. We previously identified DDR1 kinase as a direct target gene of p53. We found that, unlike other typical p53 target genes, DDR1 kinase promotes cell survival by offsetting p53-mediated apoptosis in cancer cells containing WT p53. DDR1 was originally identified in a screen for tyrosine kinase proteins expressed in human malignancies and also found as one of several major activated tyrosine kinases in a variety of human cancers. From recent functional cancer genomics efforts (Norvatis/Broad Consortium), DDR1 is amplified, and mutated in many types human malignancies, including epithelial cancers and lymphomas. However, the specific molecular mechanism(s) by which this receptor may contribute to oncogenesis remains incompletely understood. Our preliminary data show that several DDR1 mutations in human cancer cell lines appear to promote constitutively activation of DDR1 and exert resistance to broad kinase inhibitors such as dastinib and iressa. Our studies clearly demonstrate the essential role of the DDR1 pathway in maintaining cancer cell survival, proliferation and migration/invasion. Subsequently, we have identified EMT regulators as a downstream pathway of DDR1. Using integrated biochemical, therapeutic and genetic approaches in vitro and in vivo, the overall goal of this application is to elucidate the specific molecular mechanism by which DDR1 alterations contribute to tumorigenesis and pro-survival in response to genotoxic stress. We hypothesize that while p53-dependent up-regulation of DDR1 plays a protective role against genotoxic stress/DNA damage, DDR1 mutations are important oncogenic events in a subset of cancer cells that contribute to cell survival and play a role in chemo-resistance in cancer cells. Further understanding of this unexplored pathway underlying DDR1-mediated prosurvival/protective response in vitro and in vivo is expected to eventually translate into therapeutic benefits for the treatment of tumors. To test the above hypotheses, we propose the following three specific aims: firstly to investigate the functional significance and oncogenic potential of constitutive DDR1 receptor kinase activation resulting from genomic alterations in vitro and in vivo, and secondly to examine whether DDR1-deficiency results in the suppression of tumorigenesis and protective response to genotoxic stress in vivo; this aim will investigate how DDR1- deficiency contributes to mammary tumor progression and to genotoxic stress response in a genetic mouse tumor model.

描述（由适用提供）：遗传毒性/DNA损伤应激反应的中心协调员是肿瘤抑制p53，它调节与细胞周期停滞和凋亡有关的基因表达。我们先前鉴定出DDR1激酶是p53的直接靶基因。我们发现，与其他典型的p53靶基因不同，DDR1激酶通过抵消含有WT p53的癌细胞中p53介导的凋亡来促进细胞的存活。 DDR1最初是在人类恶性肿瘤表达的酪氨酸激酶蛋白的筛选中鉴定出来的，并且在各种人类癌症中也被发现是几种主要的活性酪氨酸激酶之一。从最近的功能性癌症基因组学工作（Norvatis/Broad Consortium）中，DDR1在许多类型的人类恶性肿瘤中被放大并突变，包括上皮癌和淋巴瘤。但是，该接收器可能对肿瘤发生的特定分子机制尚不完全理解。我们的初步数据表明，人类癌细胞系中的几种DDR1突变似乎促进了DDR1的组成性激活，并对诸如Dastinib和Iressa等广泛的激酶抑制剂发挥抗性。我们的研究清楚地表明，DDR1途径在维持癌细胞存活，增殖和迁移/侵袭中的重要作用。随后，我们将EMT调节剂确定为DDR1的下游途径。使用综合的生化，治疗和遗传方法在体外和体内，该应用的总体目标是阐明特定的分子机制，通过这种机制，DDR1改变有助于肿瘤生物发生和促卵巢，以响应遗传毒性应激。我们假设，尽管DDR1的p53依赖性上调对遗传毒性应激/DNA损伤起受保护的作用，但DDR1突变在癌细胞的一部分中是重要的致癌事件，这些事件有助于细胞存活并在癌细胞中的化学抗性中起作用。进一步了解DDR1介导的Provival/Prosestive反应在体外和体内预计最终将转化为治疗肿瘤的治疗益处的意外途径。为了检验上述假设，我们提出以下三个具体目的：首先，首先研究由基因组改变体外和体内基因组改变而导致的组成型DDR1受体激酶激活的功能意义和致癌潜力，其次是研究DDR1缺乏率是否在抑制肿瘤的抑制和保护毒性应力的毒素毒性中是否会导致VIVO的抑制作用;该目标将研究DDR1缺陷如何在遗传小鼠肿瘤模型中有助于乳腺肿瘤进展和遗传毒性应激反应。