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Published on: November 5, 2014
ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in
Cecilia Bergonzini1, Alessandro Gregori2,3, Tessa M S Hagens1
1Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
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.
Insights
Pancreatic cancer cells develop paclitaxel resistance via ABCB1 gene amplification. Kinase inhibitors can overcome this resistance, offering new therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer.
- Existing chemotherapies like gemcitabine/nab-paclitaxel face significant drug resistance.
- Understanding resistance mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- Investigate mechanisms of paclitaxel resistance in PDAC.
- Identify strategies to overcome paclitaxel resistance in PDAC.
- Explore novel therapeutic targets for resistant PDAC.
Main Methods:
- Established paclitaxel-resistant (PR) and gemcitabine-resistant (GR) PDAC models.
- Utilized transcriptomics and proteomics to identify resistance mechanisms.
- Employed genetic and pharmacological approaches to overcome resistance.
Main Results:
- Identified ABCB1 gene upregulation via locus amplification as a unique mechanism in PR PDAC cells.
- ABCB1 inhibition (verapamil, siRNA) sensitized PR cells to paclitaxel.
- Discovered kinase inhibitors that reduce ABCB1 substrate efflux and sensitize PR PDAC cells.
Conclusions:
- ABCB1 upregulation through locus amplification is a novel mechanism of paclitaxel resistance in PDAC.
- Kinase inhibitors show potential for overcoming paclitaxel resistance in PDAC.
- Further clinical studies of identified kinase inhibitors are warranted.
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