Erlotinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. We have recently demonstrated that gefitinib, a structurally similar receptor tyrosine kinase inhibitor, inhibited functions of ATP-binding cassette transporters. The objective of this study is to explore the combined effect of erlotinib and chemotherapeutic agents in cells that overexpress ATP-binding cassette transporters. Cells that overexpress p-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer resistant protein (MCF7/TPT300 and CL1/Tpt) and multidrug resistant-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to erlotinib. Erlotinib (0.3 to 3 μM) added to culture media had no effect on 50% inhibitory concentrations of paclitaxel, doxorubicin or etoposide in wild type MCF7 or CL1 cells. Erlotinib was synergistic with topotecan in CL1/WT cells. These concentrations of erlotinib also caused a dose-dependent reversal of resistance to topotecan in CL1/Tpt and MCF7/TPT cells. At 3μM, erlotinib completely reversed BCRP conferred topotecan resistance in these two chemoresistant cells. Erlotinib had only small reversing effect in p-glycoprotein or MRP1 overexpressing multidrug resistant cancer cells. Topotecan efflux was inhibited and accumulation was restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with 3μM of erlotinib. Our results suggest that erlotinib at a clinical attainable concentration completely reverses ABCG2 conferred resistance in multidrug resistant lung adenocarcinoma cancer cells.
Date:
2006-04
Relation:
Cancer Research. 2006 Apr;66(8, Suppl.):1273-1274.
