Effects of ATR-CHK1 inhibition on genome stability and cancer progression

ATR-CHK1 抑制对基因组稳定性和癌症进展的影响

基本信息

批准号：
9042322
负责人：
Eric J Brown
金额：
$ 39.93万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042322
关键词：
Address Affect Applications Grants Automobile Driving Breast Cancer Cell Breast Epithelial Cells CHEK1 gene Cell Survival Cells Characteristics Chromatin Collaborations Complex Cultured Cells DNA Damage DNA Double Strand Break DNA biosynthesis DNA replication fork Effectiveness Event Excision Exhibits Generations Genetic Genome Stability Growth Health Human In Vitro Intestinal Neoplasms Malignant Neoplasms Mammalian Cell Mediating Metabolism Mitosis Molecular Mus Neoplasm Transplantation Normal tissue morphology Nuclear Oncogenes PLK1 gene Pathway interactions Phosphotransferases Process Protein p53 Proteomics Radiation therapy Retrieval S Phase STK6 gene Signal Transduction Stress TP53 gene Testing Toxic effect Transplantation Tumor Suppressor Genes Ubiquitination base cancer therapy cellular engineering fibrosarcoma helicase in vivo inhibitor/antagonist malignant breast neoplasm premature prevent prognostic value response standard of care traditional therapy tumor progression ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): We have utilized hypomorphic suppression of the ATR checkpoint kinase to promote replication fork collapse into DSBs selectively in oncogene-expressing cells and those lacking the p53 tumor suppressor gene. Understanding the process of replication fork collapse is helpful in determining the ideal genetic contexts in which such therapies should be applied. Towards this objective, we have recently demonstrated that the AURKA-PLK1 pathway and the SUMO-targeted E3 ubiquitin ligase RNF4 are required for fork collapse and DSB formation when ATR is inhibited. In this grant proposal, we will 1) dissect the regulatory interrelationships between AURKA-PLK1, RNF4 and ATR in replication fork stability, 2) characterize the ubiquitination events mediated by the AURKA-PLK1 pathway and RNF4 that drive the disengagement of replication factors from the fork, and 3) determine if the amplification of AURKA activity and replisome sumoylation in human breast cancers promotes sensitivity to ATR/CHK1 inhibitors in cultured cells and orthotopically transplanted tumors in mice. These studies will advance our understanding of the causes of replication fork collapse upon ATR/CHK1 inhibition and investigate the prognostic value of amplified AURKA-PLK1 activity and replisome sumoylation in responsiveness to ATR/CHK1 inhibitor treatments.

描述（由适用提供）：我们利用了对ATR检查点激酶的低形态抑制作用，以在表达致癌基因的细胞中选择性地促进复制叉塌陷到DSB中，并且缺乏p53肿瘤抑制基因的细胞。了解复制叉倒塌的过程有助于确定应应用此类疗法的理想遗传环境。为了实现这一目标，我们最近证明了Aurka-Plk1途径和Sumo靶向的E3泛素连接酶RNF4需要在抑制ATR时叉塌陷和DSB形成。在这项赠款提案中，我们将1）剖析Aurka-Plk1，RNF4和ATR之间的调节性相互关系，以复制叉稳定性，2）表征Aurka-plk1途径和RNF4介导的泛素化事件，该事件是由福克斯（Amplification）从Fork中脱离福克斯（Amplifificative and fork and fork and fork and fork and fork and fork and fork and fork and fork and fork）介导的。人乳腺癌中的Aurka活性和复制体sumoylation促进了小鼠培养细胞和原始移植肿瘤中对ATR/CHK1抑制剂的敏感性。这些研究将提高我们对ATR/CHK1抑制剂治疗的复制叉崩溃原因的理解。