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Background <p>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 [<CitationRef CitationID="CR1">1</CitationRef>]. We have shown that P-gp/<i>ABCB1</i> influences resistance to paclitaxel and olaparib, but similar niraparib resistance mechanisms have not been described [<CitationRef CitationID="CR2">2</CitationRef>, <CitationRef CitationID="CR3">3</CitationRef>].</p> Methods <p>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. <i>ABCB1</i> and <i>ABCG2</i> 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.</p> Results <p>P-gp/<i>ABCB1</i> expression was not increased in A2780nirapR cells, which alternatively up-regulated BCRP/<i>ABCG2</i>. <i>ABCG2</i> was consistently induced in niraparib-resistant patients, but <i>ABCB1</i> only in patients pre-treated with paclitaxel. sh<i>ABCG2</i> 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.</p> Conclusions <p>Treatment-induced BCRP/<i>ABCG2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Caitlin J. Macdonald,
  • Amber McWhirter,
  • Aparajitha Vaidyanathan,
  • Michelle J. Ferguson,
  • H. Christian Eberl,
  • Euan A. Stronach,
  • Lynne Sawers,
  • Gillian Smith

摘要

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. shABCG2 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.