Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination-Proficient Pancreatic Cancer.

ABSTRACT: PARP inhibitor monotherapy (olaparib) was recently FDA approved for the treatment of BRCA1/2-mutant, homologous recombination (HR) repair-deficient pancreatic cancer. Most pancreatic cancers, however, are HR proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. Whereas catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required conc

SUBMITTER: Parsels LA 

PROVIDER: S-EPMC7867626 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature