What question did this study set out to answer?

The study aims to identify mechanisms of resistance to PARP inhibitors, particularly niraparib, in ovarian cancer following chemotherapy.

April 19, 2026British Journal of Cancer0 citationsOpen Access

Identification of novel drug-specific PARP inhibitor resistance mechanisms in ovarian cancer–implications for clinical practice

CMCaitlin J. MacdonaldUniversity of Dundee AMAmber McWhirterUniversity of Dundee AVAparajitha VaidyanathanJohns Hopkins University

Key Points

The study aims to identify mechanisms of resistance to PARP inhibitors, particularly niraparib, in ovarian cancer following chemotherapy.
Used qRT-PCR, Western blot, RNASeq, and LC-MS/MS proteomics for analysis.
Compared drug transporter expression in sensitive versus resistant cell lines.
Modified ABCB1 and ABCG2 expressions using shRNA and heterologous expression techniques.
Assessed chemosensitivity through MTT and clonogenic assays.
Conducted efflux assays to evaluate substrate specificity of transporters in polarized cells.
ABCB1 expression did not increase in niraparib-resistant cells (A2780nirapR), while BCRP/ABCG2 was up-regulated.
ABCG2 induction was found in niraparib-resistant patients, but ABCB1 was only induced in those pre-treated with paclitaxel.
Knockdown of ABCG2 re-sensitized A2780nirapR cells, whereas heterologous expression induced resistance.
Both olaparib and niraparib function as substrates for P-gp and BCRP, indicating that resistance is linked to efflux transporter regulation.

Abstract

Abstract Background Maintenance PARP inhibitor (olaparib or niraparib) treatment is commonly prescribed following carboplatin/paclitaxel chemotherapy in ovarian cancer patients, but response is compromised by adaptive drug resistance 1. We have shown that P-gp/ ABCB1 influences resistance to paclitaxel and olaparib, but similar niraparib resistance mechanisms have not been described 2, 3. Methods We used qRT-PCR, Western blot, RNASeq and LC-MS/MS proteomics analysis to compare drug transporter expression in sensitive and resistant immortalised and primary patient-derived cell lines. ABCB1 and ABCG2 expression was modified by shRNA-mediated knockdown and heterologous expression, with chemosensitivity changes assessed by MTT and clonogenic assays. Substrate specificity of P-gp and BCRP was assessed by efflux assays in polarised cells. Results P-gp/ ABCB1 expression was not increased in A2780nirapR cells, which alternatively up-regulated BCRP/ ABCG2 . ABCG2 was consistently induced in niraparib-resistant patients, but ABCB1 only in patients pre-treated with paclitaxel. sh ABCG2 re-sensitised A2780nirapR cells, while heterologous expression in A2780 cells induced drug resistance. Efflux assays confirmed that olaparib and niraparib are both P-gp and BCRP substrates, suggesting that resistance results from transcriptional regulation of efflux transporters not substrate specificity. Conclusions Treatment-induced BCRP/ ABCG2 induction is a novel clinically relevant niraparib resistance biomarker. Routine inclusion of paclitaxel in first-line chemotherapy regimens may promote efflux transporter-mediated resistance, compromising response to PARPi maintenance treatment.

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