A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers
Mohammed Alruwaili, Justin Zonneville, Maricris N. Naranjo, Hannah Serio, Thomas Melendy, Robert M. Straubinger, Bryan M. Gillard, Barbara A. Foster, Priyanka Rajan, Kristopher Attwood, Sarah Chatley, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin
Abstract
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.