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（由申请人提供）：基因毒性/DNA损伤应激反应的中心协调者是肿瘤抑制因子p53，其调节参与细胞周期停滞和细胞凋亡的基因的表达。我们之前将DDR1激酶鉴定为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 介导的细胞凋亡来促进细胞存活。酪氨酸激酶蛋白在人类恶性肿瘤中表达，并且也是多种人类癌症中几种主要的活化酪氨酸激酶之一。根据最近的功能性癌症基因组学研究（Norvatis/Broad Consortium），DDR1 在许多类型的人类恶性肿瘤中被扩增和突变。然而，我们的初步数据表明，该受体可能导致肿瘤发生的具体分子机制仍不完全清楚。人类癌细胞系中的 DDR1 突变似乎会促进 DDR1 的组成性激活，并对广泛的激酶抑制剂（如达替尼和易瑞莎）产生耐药性。我们的研究清楚地证明了 DDR1 通路在维持癌细胞存活、增殖和迁移/侵袭中的重要作用。随后，我们利用体外和体内综合生化、治疗和遗传学方法确定了 EMT 调节剂作为 DDR1 的下游途径，该应用的总体目标是阐明具体的分子机制。我们发现，虽然 DDR1 的 p53 依赖性上调对基因毒性应激/DNA 损伤具有保护作用，但 DDR1 突变在一小部分中是重要的致癌事件。有助于细胞存活并在癌细胞的化疗耐药性中发挥作用的癌细胞，进一步了解 DDR1 介导的体外和保护性反应的潜在途径。体内有望最终转化为治疗肿瘤的治疗效果为了检验上述假设，我们提出以下三个具体目标：首先研究体外基因组改变引起的组成型DDR1受体激酶激活的功能意义和致癌潜力。其次，检查 DDR1 缺陷是否会导致体内肿瘤发生的抑制和对基因毒性应激的保护性反应，该目的将研究 DDR1 缺陷如何促进乳腺肿瘤进展和基因毒性；遗传小鼠肿瘤模型中的应激反应。