Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer - PubMed
7 hours ago
- #Pancreatic Cancer
- #p53
- #Microenvironment Acidity
- p53 inactivation and acidic microenvironment contribute to pancreatic ductal adenocarcinoma (PDAC) aggressiveness and treatment resistance.
- p53 knockout (KO) alters acid-base regulation, intracellular pH (pHi), and luminal pH (pHlum) in PDAC organoids.
- p53 KO is linked to DNA damage, PARP cleavage, and increased activity of ATM, ATR, and checkpoint kinase-1.
- Combined inhibition of ATM and PARP is effective against p53 KO organoids, but acid adaptation increases resistance.
- Microenvironment acidity limits treatment response in p53-deficient PDAC by enhancing cancer cell pH homeostasis.