ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02879-8 |
| _version_ | 1797362756775575552 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Cecilia Bergonzini |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:11:04Z |
| format | Article |
| id | doaj.art-178d9e5136a64abeb42daf0ec279d03d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-08T16:11:04Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-178d9e5136a64abeb42daf0ec279d03d2024-01-07T12:54:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-01-0143111610.1186/s13046-023-02879-8ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cellsCecilia Bergonzini0Alessandro Gregori1Tessa M. S. Hagens2Vera E. van der Noord3Bob van de Water4Annelien J. M. Zweemer5Bircan Coban6Mjriam Capula7Giulia Mantini8Asia Botto9Francesco Finamore10Ingrid Garajova11Liam A. McDonnell12Thomas Schmidt13Elisa Giovannetti14Erik H. J. Danen15Leiden Academic Center for Drug Research, Leiden UniversityPhysics of Life Processes, Leiden Institute of Physics, Leiden UniversityLeiden Academic Center for Drug Research, Leiden UniversityLeiden Academic Center for Drug Research, Leiden UniversityLeiden Academic Center for Drug Research, Leiden UniversityLeiden Academic Center for Drug Research, Leiden UniversityLeiden Academic Center for Drug Research, Leiden UniversityDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU UniversityDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU UniversityProteomics and Metabolomics Lab, Fondazione Pisana Per La ScienzaProteomics and Metabolomics Lab, Fondazione Pisana Per La ScienzaMedical Oncology Unit, University Hospital of ParmaProteomics and Metabolomics Lab, Fondazione Pisana Per La ScienzaPhysics of Life Processes, Leiden Institute of Physics, Leiden UniversityDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU UniversityLeiden Academic Center for Drug Research, Leiden UniversityAbstract 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.https://doi.org/10.1186/s13046-023-02879-8Pancreatic cancerPaclitaxel resistanceABCB1Kinase-inhibitors |
| spellingShingle | 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 ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells Journal of Experimental & Clinical Cancer Research Pancreatic cancer Paclitaxel resistance ABCB1 Kinase-inhibitors |
| title | ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| title_full | ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| title_fullStr | ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| title_full_unstemmed | ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| title_short | ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| title_sort | abcb1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells |
| topic | Pancreatic cancer Paclitaxel resistance ABCB1 Kinase-inhibitors |
| url | https://doi.org/10.1186/s13046-023-02879-8 |
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