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

Journal of Experimental & Clinical Cancer Research, vol. 43, pp. 4

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.

Authors 16

1. Cecilia Bergonzini Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

2. Alessandro Gregori Aachen Physics of Life Processes

   Leiden University · Amsterdam University Medical Centers · Cancer Center Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands

   Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands

3. Tessa M. S. Hagens Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

4. Vera E. van der Noord Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

5. Bob van de Water Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

6. Annelien J.M. Zweemer Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

7. Bircan Coban Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

8. Mjriam Capula

   Amsterdam University Medical Centers · Cancer Center Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy

   Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands

9. Giulia Mantini

   Amsterdam University Medical Centers · Cancer Center Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands

10. Asia Botto

    University of Pisa · Fondazione Pisa

    Affiliation as printed

    Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy

    Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy

11. Francesco Finamore

    Fondazione Pisa

    Affiliation as printed

    Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy

12. Ingrid Garajová
    Affiliation as printed

    Medical Oncology Unit, University Hospital of Parma, Parma, Italy

13. Liam Andrew McDonnell

    Fondazione Pisa

    Affiliation as printed

    Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy

14. Thomas Schmidt Aachen Physics of Life Processes

    Leiden University

    Affiliation as printed

    Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands

15. Elisa Giovannetti corresponding

    Amsterdam University Medical Centers · Cancer Center Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy. e.giovannetti@amsterdamumc.nl

    Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands. e.giovannetti@amsterdamumc.nl

    Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy

16. Erik H.J. Danen corresponding Aachen Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. e.danen@lacdr.leidenuniv.nl

    Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands