Journal
INVESTIGATIONAL NEW DRUGS
Volume 28, Issue 4, Pages 433-444Publisher
SPRINGER
DOI: 10.1007/s10637-009-9266-0
Keywords
Multi-drug resistance; P-gp; BCRP; MRP-1; Tyrosine kinase inhibitor; Lapatinib; Erlotinib; Gefitinib; Taxane; Anthracycline
Categories
Funding
- Cancer Research Ireland [CRI 03OCO]
- Higher Education Authority
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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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