Abstract 777: GW583340 and GW2974, human EGFR and HER-2 inhibitors, reverse ABCG2- and ABCB1-mediated drug resistance

Abstract

Abstract The overexpression of ATP-binding cassette (ABC) transporters often lead to the development of multidrug resistance (MDR), resulting in chemotherapy failure. Previously, we reported that lapatinib (GW572016), a human epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinase inhibitor (TKI), modulates ABC subfamily B member 1 (ABCB1)- and ABC subfamily G member 2 (ABCG2)-mediated MDR in cancer cells. In the present study, we conducted experiments to determine if GW583340 and GW2974; structural analogues of lapatinib; could reverse ABCB1- and ABCG2-mediated MDR. Our results showed that both GW583340 and GW2974 significantly sensitized MDR cells overexpressing ABCB1 to their anticancer substrates as well as ABCG2 overexpressing cells to its substrates. Subsequently, both GW583340 and GW2974 significantly increased intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells. Similarly, both GW583340 and GW2974 significantly increased accumulation of [3H]-mitoxantrone in ABCG2 overexpressing cells. In addition, GW583340 and GW2974 significantly inhibited ABCG2-mediated transport of methotrexate in ABCG2 overexpressing membrane vesicles. Moreover, there was no significant change in the expression levels of ABCB1 and ABCG2 in the cell lines exposed to 5 μM of either GW583340 or GW2974 for 3 days. In addition, docking model predicted the binding conformation of GW583340 and GW2974 within the large cavity of the transmembrane region of homology modeled human ABCB1. We conclude that GW583340 and GW2974, at clinically achievable concentrations reverse ABCB1- and ABCG2-mediated MDR by directly blocking the drug efflux function of these transporters. These findings may be useful in developing cancer combinational therapy with EGFR TKIs in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 777. doi:1538-7445.AM2012-777