A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers

The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer. [Display omitted] •Trifluorothymidine induces DNA breaks in p53-mutant cells via post-replicative repair•PARP inhibitor enhances DNA breaks induced by trifluorothymidine, leading to cell death•Trifluorothymidine and PARP inhibitor act synergistically against p53-mutant cancers Alruwaili et al. demonstrate that p53-mutant cancer cells accumulate DNA breaks due to post-replicative removal of thymidine analogs following DNA replication. Inhibition of PARP enhances DNA damage induced by thymidine analogs, leading to cell death. These findings support a two-drug combination strategy to improve outcomes for patients with p53-mutant cancer.