Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity.

ABSTRACT: The RAD51-BRCA2 interaction is central to DNA repair through homologous recombination. Emerging evidence indicates RAD51 overexpression and its correlation with chemoresistance in various cancers, suggesting RAD51-BRCA2 inhibition as a compelling avenue for intervention. We previously showed that combining olaparib (a PARP inhibitor (PARPi)) with RS-35d (a BRCA2-RAD51 inhibitor) was efficient in killing pancreatic ductal adenocarcinoma (PDAC) cells. However, RS-35d impaired cell viability even when administered alone, suggesting potential off-target effects. Here, through multiple, integrated orthogonal biological approaches in different 2D and 3D PDAC cultures, we characterised RS-35d enantiomers, in terms of mode of action and single contributions. By differentially inhibiting both RAD51

SUBMITTER: Masi M 

PROVIDER: S-EPMC11911456 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature