ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells.
- Resource Type
- Academic Journal
- Authors
- Bergonzini C; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; Gregori A; Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands.; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands.; Hagens TMS; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; van der Noord VE; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; van de Water B; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; Zweemer AJM; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; Coban B; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.; Capula M; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands.; Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.; Mantini G; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, The Netherlands.; Botto A; Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.; Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy.; Finamore F; Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.; Garajova I; Medical Oncology Unit, University Hospital of Parma, Parma, Italy.; McDonnell LA; Proteomics and Metabolomics Lab, Fondazione Pisana Per La Scienza, San Giuliano, Pisa, Italy.; Schmidt T; Physics of Life Processes, Leiden Institute of Physics, Leiden University, Leiden, The Netherlands.; Giovannetti E; 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. e.giovannetti@amsterdamumc.nl.; Danen EHJ; Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. e.danen@lacdr.leidenuniv.nl.
- Source
- Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE
- Subject
- Language
- English
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.
(© 2023. The Author(s).)