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

Caitlin J. Macdonald; Amber Mcwhirter; Aparajitha Vaidyanathan; Michelle J. Ferguson; H. Christian Eberl; Euan A. Stronach; Lynne Sawers; Gillian Smith

doi:10.1038/s41416-026-03423-z

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

Caitlin J. Macdonald
, Amber Mcwhirter
, Aparajitha Vaidyanathan
, Michelle J. Ferguson
, H. Christian Eberl
, Euan A. Stronach
, Lynne Sawers
, Gillian Smith (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Article › peer-review

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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. 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.

Original language	English
Pages (from-to)	290-302
Journal	British Journal of Cancer
Volume	135
DOIs	https://doi.org/10.1038/s41416-026-03423-z
Publication status	Published - 17 Apr 2026

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Industrial Collaborative Awards in Science and Engineering (iCASE) Studentships for the University of Dundee
Hunter, B. (Investigator) & MacKintosh, C. (Investigator)
3/09/18 → 30/09/25
Project: Research

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

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. 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.",

author = "Macdonald, \{Caitlin J.\} and Amber Mcwhirter and Aparajitha Vaidyanathan and Ferguson, \{Michelle J.\} and Eberl, \{H. Christian\} and Stronach, \{Euan A.\} and Lynne Sawers and Gillian Smith",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

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doi = "10.1038/s41416-026-03423-z",

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T1 - Identification of novel drug-specific PARP inhibitor resistance mechanisms in ovarian cancer–implications for clinical practice

AU - Macdonald, Caitlin J.

AU - Mcwhirter, Amber

AU - Vaidyanathan, Aparajitha

AU - Ferguson, Michelle J.

AU - Eberl, H. Christian

AU - Stronach, Euan A.

AU - Sawers, Lynne

AU - Smith, Gillian

PY - 2026/4/17

Y1 - 2026/4/17

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-026-03423-z

DO - 10.1038/s41416-026-03423-z

M3 - Article

C2 - 41998207

SN - 0007-0920

VL - 135

SP - 290

EP - 302

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

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Industrial Collaborative Awards in Science and Engineering (iCASE) Studentships for the University of Dundee

Cite this