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 (p53 Mut ) cancer are largely ineffective. Here, we report a therapeutic strategy for p53 Mut 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 p53 Mut 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 p53 Mut 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 p53 Mut cancer models. These findings support a two -drug combination strategy to improve outcomes for patients with p53 Mut cancer.