Targeting the ATR pathway in p53-deficient cancers

描述(由申请人提供)：含有失活的p53突变的癌细胞表现出检查点缺陷和DNA损伤反应受损。由于p53突变在许多常见癌症中普遍存在，因此利用这些缺陷的策略预计将产生重大的临床影响。这项建议的重点是ATR途径，这是最近出现的一个关键的p53缺陷的癌细胞生存的调节器，以回应治疗药物。ATR激酶全酶被DNA损伤和DNA复制应激激活，因此对目前使用的许多抗癌药物都有反应。最近的研究揭示了控制ATR的新机制。这些洞察力为瞄准这条途径提供了新的机会。这项拟议的项目使用遗传学和生物化学方法来研究定义有能力的ATR复合体的蛋白质-蛋白质相互作用，以及常见化疗药物对复合体形成的影响。靶向ATR途径的不同上游和下游成分，包括CDK2和Chk1，其有效性将在体外和体内进行比较评估。在一项协调努力中，将对一系列已批准的药物进行筛选，以确定新的ATR激动剂。具有靶向基因改变的人体体细胞将被用于识别新药/靶向组合。将重点努力筛选促进生存的基因，以回应顺铂，顺铂是一种抗癌药物，最近发现在缺乏p53的细胞中诱导不同的生存途径。该项目的长期目标是揭示ATR调控的基本机制，新的药物靶点，以及在p53缺失的人类癌细胞中产生合成杀伤力的新策略。

DESCRIPTION (provided by applicant): Cancer cells that harbor inactivating p53 mutations exhibit checkpoint defects and impaired DNA damage responses. Because p53 mutations are prevalent in many common cancers, strategies that would exploit these defects are predicted to have significant clinical impact. This proposal is focused on the ATR pathway, which has recently emerged as a critical modulator of p53-deficient cancer cell survival in response to therapeutic agents. The ATR kinase holoenzyme is activated by DNA damage and DNA replication stress, and is therefore responsive to many of the anticancer agents currently in use. Recent studies have revealed new mechanisms by which ATR is controlled. These insights provide new opportunities to target this pathway. This proposed project employs genetic and biochemical methods to study the protein-protein interactions that define the competent ATR complex, and the effects of common chemotherapeutic agents on complex formation. The effectiveness of targeting distinct upstream and downstream components of the ATR pathway, including Cdk2 and Chk1, will be comparatively evaluated in vitro and in vivo. In a coordinated effort, a pharmacogenetic array of approved drugs will be screened to identify new ATR activators. Human somatic cells with targeted genetic alterations will be used to identify new drug/target combinations. A focused effort will be made to screen for genes that promote survival in response to cisplatin, an anticancer drug recently found to induce distinct survival pathways in cells that are deficient for p53. The long-term objectives of this project are to reveal basic mechanisms of ATR regulation, new drug targets, and new strategies for generating synthetic lethality in p53-deficient human cancer cells.