Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer

iScience 2026 Open access

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Authors: Renata Ialchina, Thomas René Simonsen, Henriette Berg Andersen, Arnaud Stigliani, Yifan Dai, Jiayi Yao, Tanja Larsen, Dominika Czaplińska, Luis A. Pardo, Albin Sandelin, Stine F. Pedersen
DOI: 10.1016/j.isci.2026.115112
Cited by: 1
References: 70

Abstract

observed in organoids adapted to microenvironment acidity. p53 KO is associated with DNA damage, poly-ADP-ribose-polymerase (PARP) cleavage, and increased expression and/or activity of kinases Ataxia telangiectasia mutated (ATM), Ataxia-telangiectasia-and-Rad3-related (ATR), and checkpoint kinase-1. Whereas p53 KO organoids are sensitive to the combined inhibition of ATM and PARP, acid adaptation partially rescues this phenotype, increasing treatment resistance in a manner partially restored by the combined inhibition of pH-regulatory transporters. We conclude that p53 loss rewires acid-base homeostasis and that microenvironment acidity limits treatment response in p53-deficient PDAC, possibly by increasing cancer cell pH homeostasis capacity.

Fields of Study & Subjects

Cancer Hypoxia and Metabolism Enzyme function and inhibition Amino Acid Enzymes and Metabolism

Publication details

Journal / source
iScience
Publisher
Elsevier BV
Volume
29
Issue
3
Pages
115112–115112
Publication date
20 February 2026
Language
EN