Author:
Bergonzini Cecilia,Gregori Alessandro,Hagens Tessa M. S.,van der Noord Vera E.,van de Water Bob,Zweemer Annelien J. M.,Coban Bircan,Capula Mjriam,Mantini Giulia,Botto Asia,Finamore Francesco,Garajova Ingrid,McDonnell Liam A.,Schmidt Thomas,Giovannetti Elisa,Danen Erik H. J.
Abstract
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.
Funder
KWF Kankerbestrijding
Associazione Italiana per la Ricerca sul Cancro
Cancer Center Amsterdam
Fondazione Pisana per la Scienza
European Organisation for Research and Treatment of Cancer
Publisher
Springer Science and Business Media LLC