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

Autor:	Alruwaili MM; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Department of Medical Laboratory Technology, College of Applied Medical Science, Northern Border University, Arar City, Saudi Arabia., Zonneville J; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Naranjo MN; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Serio H; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Melendy T; Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY 14214, USA., Straubinger RM; Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Gillard B; Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA., Foster BA; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Rajan P; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Attwood K; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Chatley S; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Iyer R; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA., Fountzilas C; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: christos.fountzilas@roswellpark.org., Bakin AV; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address: andrei.bakin@roswellpark.org.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Mar 19; Vol. 5 (3), pp. 101434. Date of Electronic Publication: 2024 Feb 21.
DOI:	10.1016/j.xcrm.2024.101434
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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