Synergistic Combinations of Small Molecule Kinase Inhibitors: Implications for Reducing Toxicities in Nasopharyngeal Carcinoma Treatment

Abstract

Purpose: Overexpression of epidermal growth factor receptor (EGFR) occurs in nasopharyngeal carcinoma (NPC) but targeting EGFR with gefitinib or erlotinib has not been effective in treating NPC. Our aim is to determine combination of kinase inhibitors which are effective. Materials and Methods: The viability of NPC cell lines (TW01, TW04, and TW06) was assessed using MTT assay. Dual targeting of EGFR, IGF-1R, mTORC, and PI3K with gefitinib, NVP-AEW541, KU0063794, and NVP-BKM120, respectively, was performed. Results: Combination index calculations by the Chou-Talalay method demonstrated synergism in three out of six possible combinations in NPC cell lines. The effective combinations were KU0063794 (mTORC inhibitor) with gefitinib, or NVP-AEW541 (IGF-1R inhibitor) and gefitinib with NVP-AEW541. No combination was found to be antagonistic. In these synergistic combinations, dose-reduction index revealed a considerable decrease in the inhibitor concentration, as compared to that in the single treatments. Noticeably, NVP-AEW541 dose was reduced by 5.3- to 8.8-fold when combined with KU0063794. With NVP-AEW541 plus gefitinib, the dose of NVP-AEW541 was reduced by up to 7.3-fold. The dose of gefitinib was reduced by up to 8.4-fold in the combination with KU0063794. This dose reduction implies a decrease in the likelihood of intolerable toxicities while maintaining their therapeutic efficacy. Conclusions: Our data shows that three appropriate dual combinations (KU0063794 with gefitinib, or NVP-AEW541, and gefitinib with NVP-AEW541) are potentially relevant for treating NPC.