Abstract 1519: Tyrosine kinase inhibitors are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC ATP binding cassette (ABC) transporters play a crucial role in the development of multidrug resistance (MDR) leading to failure of the cancer chemotherapy. Previously, we and others have reported that lapatinib, erlotinib (EGFR tyrosine kinase inhibitors/TKIs) and nilotinb, imatinib (BCR-Abl TKIs) reverse ABCB1- and ABCG2-mediated MDR. MRP7/ABCC10, a member of MRP family, shares a structural homology with other ABC transporters such as P-gp/ABCB1. MRP7 is involved in effluxing several anticancer drugs resulting in poor chemotherapeutic outcome. In an effort to reverse MRP7-mediated MDR, we discovered that EGFR TKIs lapatinib, erlotinib, and BCR-Abl TKIs imatinib, nilotinib enhances the sensitivity of MRP7-transfected HEK293 (HEK-MRP7-2) cells to the established MRP7 substrates, such as paclitaxel, docetaxel, vincristine and vinorelbine in concentration-dependent manner. However, there was no significant effect of these TKIs on the sensitivity of control HEK293-pcDNA3.1 cells. In addition, these TKIs increased the intracellular accumulation of [3H]paclitaxel, inhibiting MRP7-mediated [3H]paclitaxel efflux from HEK-MRP7-2 cells. Moreover, Western blot analysis showed no significant change in the MRP7 expression level in the MRP7 overexpressing cell line on treatment with aforementioned TKIs. We conclude that both EGFR TKIs (lapatinib, erlotinib) and BCR-Abl TKIs (imatinib, nilotinib) reverse MRP7-mediated MDR through inhibition of the drug efflux function of MRP7, suggesting that TKI based combinational chemotherapy may be useful in cancer clinical practice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1519.