Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma.

ABSTRACT:

Background

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer. While DNA damaging agents such as platinum and PARP inhibitors have derived clinical benefits, acquired resistance invariably develops. Hence there is an urgent need for novel therapeutic strategies to overcome acquired resistance.

Methods

Clinically relevant resistance in PDAC patient-derived cell lines was achieved by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity, flow cytometry, immunofluorescence, and transcriptomic analysis were used to investigate the efficacy of ATR (ceralasertib) and PARP (olaparib) inhibitors in overcoming acquired resistance.

Results

Acquired resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, me

SUBMITTER: Herbert KJ 

PROVIDER: S-EPMC12322129 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature