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Modulation of P-gp expression by lapatinib

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Summary

Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance.

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Acknowledgements

This work was supported by funding from Ireland’s Higher Educational Authority Program for Research in Third Level Institutions (PRTLI) Cycle 4 and the Science Foundation Ireland Strategic Research Cluster award to Molecular Therapeutics for Cancer Ireland (award 08/SRC/B1410)

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Authors and Affiliations

  1. National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland

    Gráinne Dunne, Laura Breen, Denis M. Collins, Sandra Roche, Martin Clynes & Robert O’Connor

  2. School of Nursing, Dublin City University, Glasnevin, Dublin 9, Ireland

    Robert O’Connor

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  1. Gráinne Dunne
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  2. Laura Breen
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  3. Denis M. Collins
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  4. Sandra Roche
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Correspondence to Laura Breen.

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Dunne, G., Breen, L., Collins, D.M. et al. Modulation of P-gp expression by lapatinib. Invest New Drugs 29, 1284–1293 (2011). https://doi.org/10.1007/s10637-010-9482-7

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