Implications of the ATR Checkpoint Kinase in Radiation and Targeted Therapies

 描述（由申请人提供）：基因组不稳定性是癌症的标志。基因不稳定的癌细胞通常对放疗和化疗敏感。辐射通过造成多种类型的DNA损伤来杀死癌细胞，包括DNA双链断裂（DSB）。DSB修复缺陷的癌细胞，如携带BRCA 1/2突变的癌细胞，对辐射高度敏感。BRCA 1/2缺陷细胞也对PARP抑制剂敏感，这为提高放射治疗的疗效提供了一种新的策略。然而，BRCA 1缺陷型癌细胞由于在同源重组（HR）中绕过BRCA 1而经常获得对辐射和PARP抑制剂的抗性，从而阻碍了BRCA 1缺陷型癌症的治疗。这些发现提出了一些重要的问题，如BRCA 1非依赖性HR与BRCA 1依赖性HR有何不同，以及BRCA 1缺陷细胞的辐射和PARP抑制剂抗性是否可以克服。我们最近对主检查点激酶ATR的研究为这些问题提供了重要线索。我们发现，在BRCA 1-proficient细胞，ATR磷酸化BRCA 1和控制其下游功能的HR。令人惊讶的是，即使在BRCA 1缺陷细胞的BRCA 1的功能被绕过，ATR仍然是HR的关键，这表明一个BRCA 1的ATR在辐射反应中的独立作用。基于这些令人兴奋的发现，我们假设ATR通过BRCA 1依赖和非依赖机制调节HR。此外，ATR抑制可能是克服BRCA缺陷肿瘤的辐射和PARP抑制剂抗性的有效方法。我们建议：1）阐明ATR如何通过磷酸化BRCA 1调节HR; 2）揭示ATR如何调节BRCA 1非依赖性HR; 3）系统地测试ATR抑制剂是否可广泛用于克服BRCA缺陷肿瘤的辐射和PARP抑制剂抗性。

 DESCRIPTION (provided by applicant): Genomic instability is a hallmark of cancer. Cancer cells that are genetically unstable are often susceptible to radiation and chemotherapy. Radiation kills cancer cells by inflicting multiple types of DNA damage, including DNA double-stranded breaks (DSBs). Cancer cells defective for DSB repair, such as those carrying BRCA1/2 mutations, are highly sensitive to radiation. BRCA1/2-deficient cells are also sensitive to PARP inhibitors, presenting a new strategy to improve the efficacy of radiation therapy. However, BRCA1-deficient cancer cells often acquire resistance to radiation and PARP inhibitors due to the bypass of BRCA1 in homologous recombination (HR), hindering the treatment of BRCA1-deficient cancers. These findings raised important questions as to how BRCA1-independent HR differs from BRCA1-dependent HR, and whether the radiation and PARP inhibitor resistance of BRCA1-deficient cells can be overcome. Our recent studies on the master checkpoint kinase ATR have provided important clues to these questions. We found that in BRCA1-proficient cells, ATR phosphorylates BRCA1 and controls its downstream functions in HR. Surprisingly, even in BRCA1- deficient cells where the function of BRCA1 is bypassed, ATR is still critical for HR, suggesting a BRCA1- independent role for ATR in the radiation response. Based on these exciting findings, we hypothesize that ATR regulates HR via both BRCA1-dependent and -independent mechanisms. Furthermore, ATR inhibition may be an effective way to overcome the radiation and PARP inhibitor resistance of BRCA-deficient tumors. We propose to: 1) elucidate how ATR regulates HR by phosphorylating BRCA1; 2) reveal how ATR regulates BRCA1-independent HR; and 3) systematically test if ATR inhibitors can be broadly used to overcome the radiation and PARP inhibitor resistance of BRCA-deficient tumors.