Chronic exposure to the novel PARP inhibitor niraparib (ZEJULA®), in contrast to olaparib, limits the impact of chemotherapy-induced multidrug resistance in ovarian cancer


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Gillian Smith1,Aparajitha Vaidyanathan1,Amber McWhirter1,Lynne Sawers1,Susan Bray1,Kaiming Sun2,Jing Yu Wang2,Michelle Ferguson3
1University of Dundee,2TESARO,3NHS Tayside

Abstract

Background

Ovarian cancer is routinely treated with combination carboplatin/paclitaxel chemotherapy, but durable response is frequently compromised by chemotherapy-induced resistance. Increased P-glycoprotein (P-gp)-mediated drug efflux promotes paclitaxel-induced resistance in ovarian cancer. Using novel drug-resistant cell lines to mimic responses in sensitive and resistant patients, we have shown that ABCB1 (MDR1; P-glycoprotein) induction defines a common resistance mechanism which limits efficacy of both paclitaxel and the PARP inhibitor olaparib. We now investigate whether this mechanism is common to additional PARP inhibitors including niraparib, recently licensed for maintenance treatment of relapsed platinum-sensitive disease.

Method

A2780 ovarian cancer cells were made resistant to paclitaxel (A2780pacR), olaparib (A2780olapR) and niraparib (A2780nirapR), with drug treatments designed to mimic typical clinical steady state peak plasma levels. MTT chemosensitivity and clonogenic assays were used to compare sensitivity of parental and resistant cells to paclitaxel, olaparib, rucaparib and niraparib; qRT-PCR and Western blot analysis to compare ABCB1 mRNA and P-gp expression, and P-gp ATP-ase assays to assess whether PARP inhibitors were strong or weak P-gp substrates.

Results

Consistent with pre-clinical data, niraparib was more potent than either olaparib or rucaparib in both 72-96h MTT and 6-day clonogenic assays, with cross-resistance to paclitaxel significantly reduced in comparison to olaparib or rucaparib. In contrast to olaparib, niraparib did not influence P-glycoprotein ATP-ase activity, and A2780nirapR cells did not express P-glycoprotein.

Conclusion

Our data confirms that niraparib is more potent than either olaparib or rucaparib in A2780pacR and A2780olapR cells, in part as efficacy is not limited by P-gp-mediated drug efflux. Routine first-line treatment of ovarian cancer patients with paclitaxel may therefore limit clinical response to PARP inhibitors, although the influence of P-gp-mediated drug efflux may be avoided by prescription of niraparib. Studies to investigate novel P-gp-independent mechanisms of niraparib resistance are underway in our laboratory.