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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Verapamil | Research

ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells

Authors: Cecilia Bergonzini, Alessandro Gregori, Tessa M. S. Hagens, Vera E. van der Noord, Bob van de Water, Annelien J. M. Zweemer, Bircan Coban, Mjriam Capula, Giulia Mantini, Asia Botto, Francesco Finamore, Ingrid Garajova, Liam A. McDonnell, Thomas Schmidt, Elisa Giovannetti, Erik H. J. Danen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer and the chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim of this study was to investigate mechanisms underlying paclitaxel resistance in PDAC and explore strategies to overcome it.

Methods

Three paclitaxel (PR) and gemcitabine resistant (GR) PDAC models were established. Transcriptomics and proteomics were used to identify conserved mechanisms of drug resistance. Genetic and pharmacological approaches were used to overcome paclitaxel resistance.

Results

Upregulation of ABCB1 through locus amplification was identified as a conserved feature unique to PR cells. ABCB1 was not affected in any of the GR models and no cross resistance was observed. The ABCB1 inhibitor verapamil or siRNA-mediated ABCB1 depletion sensitized PR cells to paclitaxel and prevented efflux of ABCB1 substrates in all models. ABCB1 expression was associated with a trend towards shorter survival in patients who had received gemcitabine/nab-paclitaxel treatment. A pharmacological screen identified known and novel kinase inhibitors that attenuate efflux of ABCB1 substrates and sensitize PR PDAC cells to paclitaxel.

Conclusion

Upregulation of ABCB1 through locus amplification represents a novel, conserved mechanism of PDAC paclitaxel resistance. Kinase inhibitors identified in this study can be further (pre) clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.
Appendix
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Metadata
Title
ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells
Authors
Cecilia Bergonzini
Alessandro Gregori
Tessa M. S. Hagens
Vera E. van der Noord
Bob van de Water
Annelien J. M. Zweemer
Bircan Coban
Mjriam Capula
Giulia Mantini
Asia Botto
Francesco Finamore
Ingrid Garajova
Liam A. McDonnell
Thomas Schmidt
Elisa Giovannetti
Erik H. J. Danen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-023-02879-8

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