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

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT Aims Chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance in pancreatic ductal adenocarcinoma (PDAC). We aimed to identify novel actionable mechanisms to overcome such resistance. 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 detected in PDAC patients that 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. ABCB1 has not been previously implicated in PR PDAC. The synthetic lethal interactions identified in this study can be further (pre)clinically explored as therapeutic strategies to overcome paclitaxel resistance in PDAC.

Authors 15

1. Cecilia Bergonzini Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

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

7. 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

8. 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

9. Asia Botto

   Fondazione Pisa

   Affiliation as printed

   Proteomics and Metabolomics Lab, Fondazione Pisana per la Scienza, San Giuliano, Pisa, Italy

10. Francesco Finamore

    Fondazione Pisa

    Affiliation as printed

    Proteomics and Metabolomics Lab, Fondazione Pisana per la Scienza, San Giuliano, Pisa, Italy

11. Ingrid Garajová
    Affiliation as printed

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

12. Liam Andrew McDonnell

    Fondazione Pisa

    Affiliation as printed

    Proteomics and Metabolomics Lab, Fondazione Pisana per la Scienza, San Giuliano, Pisa, Italy

13. Thomas Schmidt Aachen Physics of Life Processes

    Leiden University

    Affiliation as printed

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

14. 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

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

15. 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, The Netherlands