43eP NRF2 inhibition restores sensitivity to olaparib in resistant SKOV3 ovarian cancer cells

Abstract

Acquired resistance to olaparib, a PARP inhibitor, represents a major challenge in the treatment of high grade ovarian cancer. Activation of the KEAP1-NRF2 pathway has been identified as a key mechanism in drug resistance. NRF2 regulates the expression of antioxidant and cytoprotective genes, including HO-1 and NQO1, promoting cell survival under oxidative stress. To assess this study, olaparib-sensitive and -resistant SKOV3 high grade ovarian cancer cells were used. Acquired resistance was induced through prolonged and repeated exposure of the parental SKOV3 cell line to olaparib, resulting in the SKOV3R cell line. Half-maximal inhibitory concentration (IC50) values were determined by MTT viability assays. Both lines were treated with olaparib at IC50 value obtained for SKOV3, and expression levels of KEAP1, NRF2, HO-1, and NQO1 were analyzed via RT-qPCR. Inhibition of NRF2 pathway was performed with NRF2 inhibitor ML385. Combination studies with ML385 and olaparib were performed at a 1:1 ratio to assess potential synergistic effects on IC50 by MTT.