DNA Damage Response inhibitors as a new therapeutic opportunity in colorectal cancer

Targeting the DNA damage response (DDR) represents an emergent and promising therapeutic strategy for cancer treatment. For this reason, different DDR inhibitors are currently under clinical development. However, at this moment, only poly-ADP ribose polymerase (PARP) inhibitors are approved in the clinic for the treatment of breast, ovarian, pancreatic and prostate cancer, while in colorectal cancer (CRC) the efficacy of these class of compounds is still being evaluated. In this work, we tested seven DDR inhibitors targeting PARP, ATM, ATR, CHK1, WEE1 and DNA-PK in 112 CRC cell lines, which recapitulate the molecular landscape of CRC, and 5 CRC patient-derived organoids. Efficacy of each inhibitor was observed in a subset of CRC models, including those considered undruggable with anti-EGFR antibodies due to alterations in the RAS/RAF pathway. Biochemical and functional analysis revealed potential biomarkers of response to the DDR inhibitors. For example we found that ATM, RAD51 and RAD51C loss confer sensitivity to both olaparib and ATR inhibitors. In conclusion, this study suggests that targeting the DDR might represent a new therapeutic opportunity in CRC patients, including those that are refractory to current treatment regimens.