%0 Journal Article
%T A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers.
%A Alruwaili MM
%A Zonneville J
%A Naranjo MN
%A Serio H
%A Melendy T
%A Straubinger RM
%A Gillard B
%A Foster BA
%A Rajan P
%A Attwood K
%A Chatley S
%A Iyer R
%A Fountzilas C
%A Bakin AV
%J Cell Rep Med
%V 5
%N 3
%D 2024 Mar 19
%M 38387463
%F 16.988
%R 10.1016/j.xcrm.2024.101434
%X 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.