Synergistic Effects of Olaparib and Palbociclib in Resistant epithelial ovarian cancer.

Abstract

This study investigates the mechanisms of poly ADP-ribose polymerase inhibitor (PARPi) resistance in epithelial ovarian cancer (EOC). It also explores strategies to overcome this resistance by combining PARPi with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). EOC cell lines A2780 and SKOV-3 were treated with PARPi to develop stable drug-resistant cell lines, A2780-ola-r and SKOV-3-ola-r. Low-dose treatments with Olaparib, Palbociclib, and their combination significantly reduced tumor proliferation in these resistant cells. Bioinformatics analysis identified potential therapeutic targets, KNSTRN and TRPC4AP. The combination treatment induced G1 phase cell cycle arrest at low drug concentrations. Immunofluorescence studies demonstrated reduced nuclear RAD51 and increased p-γH2AX levels following combination or Palbociclib treatment, compared to DMSO. Western blot analysis revealed elevated expression of homologous recombination repair (HRR) pathway-related proteins in the resistant cell lines. Post-treatment analysis indicated a negative correlation between KNSTRN levels and the efficacy of CDK4/6i or combination therapy, whereas TRPC4AP levels positively correlated with treatment response. These findings offer critical insights into the mechanisms of PARPi resistance in EOC and suggest that combining PARPi with CDK4/6i is a promising therapeutic strategy to overcome this resistance and improve outcomes for patients with EOC.