Implications of the ATR Checkpoint Kinase in Radiation and Targeted Therapies

 描述(申请人提供)：基因组不稳定是癌症的一个标志。基因不稳定的癌细胞往往容易受到放射和化疗的影响。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，如那些携带BRCA1/2突变的癌细胞，对辐射高度敏感。BRCA1/2缺陷细胞对PARP抑制剂也很敏感，这为提高放射治疗的疗效提供了一种新的策略。然而，由于BRCA1在同源重组(HR)中的旁路，BRCA1缺陷的癌细胞往往对辐射和PARP抑制剂产生抵抗力，阻碍了BRCA1缺陷肿瘤的治疗。这些发现提出了重要的问题，即BRCA1依赖的HR与BRCA1依赖的HR有何不同，以及BRCA1缺陷细胞的辐射和PARP抑制剂耐药性是否可以克服。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的线索。我们发现，在精通BRCA1的细胞中，ATR磷酸化BRCA1并控制其在HR中的下游功能。令人惊讶的是，即使在BRCA1功能被绕过的BRCA1缺陷细胞中，ATR仍然对HR至关重要，这表明ATR在辐射反应中起着不依赖BRCA1的作用。基于这些令人兴奋的发现，我们假设ATR通过BRCA1依赖和非独立机制来调节HR。此外，ATR抑制可能是克服BRCA缺陷肿瘤放射和PARP抑制剂耐药性的有效方法。我们建议：1)阐明ATR如何通过磷酸化BRCA1来调节HR；2)揭示ATR如何调节BRCA1非依赖性HR；3)系统地测试ATR抑制剂是否可以广泛用于克服BRCA缺陷肿瘤的放射和PARP抑制剂耐药性。

 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.