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.
Genomic instability is a hallmark of cancer and an attractive target for therapy. We will investigate how ATR, a master DNA damage-signaling kinase in human cells, regulates the repair of radiation induced DNA breaks. Furthermore, we will explore how to attack specific vulnerabilities of cancer cells by inhibiting ATR.
