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

• DOI: 10.1016/j.xcrm.2024.101434
• Publication Date: 2024-02-21T15:32:58Z
• Authors: Mohammed M. Alruw...; Justin Zonneville; Maricris N. Naranjo; Hannah Serio; Thomas Melendy; Robert M. Straubi...; Bryan Gillard; Barbara A. Foster; Priyanka Rajan; Kristopher Attwood; Sarah Chatley; Renuka Iyer; Christos Fountzilas; Andrei V. Bakin
• Keywords: Pancreatic Neoplasms; DNA Repair; Humans; DNA; Tumor Suppressor Protein p53; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Colorectal Neoplasms; Article; Thymidine

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.