Grant: CIHR Fellowship

Hereditary or somatic mutations in either BRCA1 or BRCA2 (BRCA1/2) genes greatly increase susceptibility to breast and ovarian cancers, and are recovered in 10-15% of cases. In addition, 60% of individuals carrying dysfunctional BRCA1/2 will be diagnosed with cancer before the age of 70. BRCA1/2 participate in the DNA damage response (DDR), thereby maintaining genomic stability and forestalling carcinogenesis. BRCA1/2-deficient cells are especially sensitive to further impairment of the DDR, providing a weakness that can be exploited to greatly increase selectivity in cancer treatment. Indeed, previous findings showed that PARP inhibitors (PARPi) can be used to take advantage of such weakness and efficiently kill BRCA1/2-deficient cancer cells. In fact, several PARPi have been approved by Health Canada for treatment of BRCA1/2-deficient breast/ovarian cancers. However, while initial response is often positive, PARPi-resistant cancer cells eventually emerge thus limiting the long-term efficacy of the treatment. It was recently shown that BRCA1-deficient cells overcome PARPi sensitivity by rewiring their DDR to bypass the need for BRCA1 in a way that is increasingly reliant on another DDR protein, ATR. Strikingly, the Zou laboratory demonstrated ATR inhibitors (ATRi) re-sensitized PARPi-resistant cells to PARPi. This highlights a promising combinatorial (ATRi/PARPi) approach for cancer treatment. However, our knowledge of the underlying molecular mechanisms is incomplete. We therefore aim to comprehensively elucidate the molecular basis of ATR function to understand how ATRi can be used for the treatment of breast and ovarian cancers.