Abstract
Abstract Background: ARRY-334543, an ATP-competitive, selective, reversible small molecule tyrosine kinases inhibitor of ErbB1 and ErbB2, has shown superior preclinical tumor inhibitory activity to that of lapatinib in a wide range of tumor cell lines and xenografts dependent on ErbB signaling pathway. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters, a major obstacle to successful cancer treatment. Material and Methods: Lung cancer cell line NCI-H460 and its drug-selected derivative ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for this study. Results: Our results found that ARRY-334543 at 1.0 µmol/l significantly reversed ABCG2-mediated multidrug resistance (MDR) through directly inhibiting the drug efflux function of ABCG2, therefore resulting in the elevated intracellular accumulation of chemotherapeutic drugs in both the drug-selected derivative ABCG2-overexpressing NCI-H460/MX20 and ABCG2-overexpressing transfected cell lines, as well as the NCI-H460, which intrinsically expressed low level of ABCG2, whereas ARRY-334543 at 1.0 µmol/l only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR. However, ARRY-334543 at reversal concentration did not affect the expression levels of ABCG2 protein. Moreover, ARRY-334543 did not regulate the re-localization of ABCG2 from cell membrane to the cytoplasm. Conclusion: We concluded that ARRY-334543 (1.0 μmol/l) significantly reversed drug resistance mediated by ABCG2. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B112. Citation Format: De-Shen Wang, Atish Patel, Priyank Kumar, Rui-Hua Xu, Zhe-Sheng Chen. ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B112.
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