Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy-mediated drug resistance in ovarian cancer cells, xenografts, and patient-derived xenograft models

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate significant activity against ovarian cancer but are often limited by acquired drug resistance. This study investigates the role of autophagy in modulating ovarian cancer cell sensitivity to PARP inhibitors.
Methods: Autophagy induction was assessed using punctate LC3 fluorescence staining, LC3I-to-LC3II conversion via Western blot, and electron microscopy. Growth inhibition and apoptosis were enhanced when PARP inhibitors were combined with hydroxychloroquine, chloroquine (CQ), or LYS05 to block autophagosome degradation, or with small interfering RNA targeting ATG5 or ATG7 to prevent autophagosome formation. The combination of CQ and olaparib was evaluated in a patient-derived xenograft (PDX) model and the OVCAR8 ovarian cancer cell line.
Results: Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in ovarian cancer cells. Inhibiting autophagy with CQ increased cell sensitivity to PARP inhibitors. In vivo, CQ and olaparib exhibited additive growth suppression in OVCAR8 xenografts and PDX models. Olaparib suppressed PARP activity, leading to increased reactive oxygen species (ROS) and γ-H2AX accumulation. Autophagy inhibition further elevated ROS and γ-H2AX levels, amplifying olaparib’s effects. Additionally, olaparib treatment activated ATM and PTEN phosphorylation while reducing AKT and mTOR phosphorylation, triggering autophagy.
Conclusions: Autophagy induced by PARP inhibitors serves as an adaptive resistance mechanism in BRCA-wild-type ovarian cancer cells. Combining PARP inhibitors with CQ or other autophagy inhibitors may enhance therapeutic efficacy and improve patient outcomes.