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

Bergonzini, C.; Gregori, A.; Hagens, T. M. S.; van der Noord, V. E.; van de Water, B.; Zweemer, A. J. M.; Capula, M.; Mantini, G.; Botto, A.; Finamore, F.; Garajova, I.; McDonnell, L. A.; Schmidt, T.; Giovannetti, E.; Danen, E. H. J.

doi:10.1101/2023.05.30.542412

bioRxiv · 10.1101/2023.05.30.542412

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

Bergonzini, C.·Gregori, A.·Hagens, T. M. S.·van der Noord, V. E.·van de Water, B.·Zweemer, A. J. M.·Capula, M.·Mantini, G.·Botto, A.·Finamore, F.·Garajova, I.·McDonnell, L. A.·Schmidt, T.·Giovannetti, E.·Danen, E. H. J.

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Abstract

AimsChemotherapies 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. MethodsThree 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. ResultsUpregulation 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. ConclusionUpregulation 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.

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Bergonzini, C., Gregori, A., Hagens, T. M. S., van der Noord, V. E., van de Water, B., Zweemer, A. J. M., Capula, M., Mantini, G., Botto, A., Finamore, F., Garajova, I., McDonnell, L. A., Schmidt, T., Giovannetti, E., Danen, E. H. J.. 2023-05-30. ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells. https://doi.org/10.1101/2023.05.30.542412

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