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

Tumor suppressor p53 inactivation and an acidic microenvironment are pancreatic ductal adenocarcinoma (PDAC) characteristics supporting disease aggressiveness and treatment resistance. Using murine early PDAC (PanIN) organoids and CRISPR-Cas9 knockout (KO) of p53, we show that the molecular acid-base regulation machinery, intracellular pH (pHi), and luminal pH (pHlum) are profoundly altered by p53 KO, which rescues the decreased pHi and pHlum 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.