Summary
To investigate the interactions of Epidermal Growth Factor Receptor (EGFR)-inhibiting tyrosine kinase inhibitors (TKIs) on P-gp-mediated drug resistance, we tested three TKIs, lapatinib, gefitinib and erlotinib in direct ATPase assays and in Non-Small Cell Lung Cancer (NCSLC) cell lines with defined low levels of growth factor receptor expression. The three TKIs potentiated the action of known P-gp substrate cytotoxic drugs at therapeutically-relevant concentrations. However, more detailed analysis revealed that the interaction of lapatinib with P-gp was distinct from that of gefitinib and erlotinib, and was characterised by direct inhibition of the stimulated P-gp ATPase activity. Lapatinib proved the most potent P-gp modulator of the TKIs examined. Drug transport studies in the P-gp-over-expressing A549-Taxol cell line showed that lapatinib and erlotinib are capable of increasing docetaxel accumulation at clinically achievable concentrations. Combination studies with P-gp substrate chemotherapeutic agents, demonstrated that all three TKIs have significant potential to augment cytotoxic activity against P-gp-positive malignancies, however, interestingly, these agents also potentiated the toxicity of epirubicin in non-P-gp resistant parental cells. Our observations suggest that the combination of lapatinib with a taxane or anthracycline warrants clinical investigation in NSCLC to examine if beneficial or detrimental interactions may result.
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Acknowledgements
Lapatinib and Elacridar were kindly provided by GlaxoSmithKline. This work was made possible by a PRTLI cycle III award from the Higher Education Authority and funding from Cancer Research Ireland (CRI 03OCO).
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Collins, D.M., Crown, J., O’Donovan, N. et al. Tyrosine kinase inhibitors potentiate the cytotoxicity of MDR-substrate anticancer agents independent of growth factor receptor status in lung cancer cell lines. Invest New Drugs 28, 433–444 (2010). https://doi.org/10.1007/s10637-009-9266-0
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DOI: https://doi.org/10.1007/s10637-009-9266-0