Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.

ABSTRACT:

Objective

ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).

Design

Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.

Results

Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null bac

SUBMITTER: Gout J 

PROVIDER: S-EPMC7948173 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature