Abstract C98: Quizartinib (AC220) potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates.

Abstract

Abstract Quizartinib (AC220), a novel and potent class II receptor tyrosine kinase inhibitor that has better therapeutic and pharmacokinetic profile amongst its class. Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. This study examined the effects of quizartinib on ABC transporter-mediated multidrug resistance (MDR). Cytotoxic studies showed that 0.75, 1.5, and 3 μM are the three less toxic concentrations for normal as well as cancer cells. Out of these three concentrations, quizartinib at 3 μM showed a significant reversal of MDR mediated by ABCG2 and ABCB1 in different MDR cell models, when compared to the positive controls, fumetrimorgin C and verapamil at 3 μM, respectively. Interestingly, quizartinib did not show a significant reversal of the MDR associated with the two mutants (R482T and R482G) ABCG2 overexpression. Results also showed that quzartinib at 3 μM significantly reversed wild-type ABCG2-mediated drug resistance by antagonizing the drug efflux function of wild-type ABCG2 and increasing the intracellular accumulation of [3H]-mitoxantrone in wild-type ABCG2-overexpressing cells. However, quizartinib at 3 μM did not reverse ABCC1- and ABCC10-mediated drug resistance in HEK/ABCC1 and HEK/ABCC10 cell lines. Hence these results conclude that quizartinib potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C98. Citation Format: Priyank Kumar, Rishil J. Kathawala, Hui Zhang, Nagaraju Anreddy, Yanglu Chen, Kanav Gupta, Louis D. Trombetta, Zhe S. Cheng. Quizartinib (AC220) potentiates the antineoplastic activity of wild-type ABCG2 and ABCB1 substrates. [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 C98.