Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells

// Tomoya Aikawa 1 , Noriko Togashi 1 , Koichi Iwanaga 1 , Hiroyuki Okada 1 , Yumi Nishiya 1 , Shinichi Inoue 1 , Mark J. Levis 2 and Takeshi Isoyama 1 1 Daiichi Sankyo Co., Ltd., Tokyo, Japan 2 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, United States of America Correspondence to: Takeshi Isoyama, email: isoyama.takeshi.y5@daiichisankyo.co.jp Keywords: relapsed/refractory AML; FLT3 inhibitors; quizartinib; AC886; midostaurin resistance Received: November 20, 2019     Accepted: January 29, 2020     Published: March 17, 2020 ABSTRACT FLT3 internal tandem duplication (ITD) mutations are associated with poor prognosis in patients with acute myeloid leukemia (AML). In this preclinical study, we characterized the binding affinity and selectivity of quizartinib, a small-molecule inhibitor of FLT3, and AC886, the active metabolite of quizartinib, compared with those of other FLT3 inhibitors. Selectivity profiling against >400 kinases showed that quizartinib and AC886 were highly selective against FLT3. Quizartinib and AC886 inhibited FLT3 signaling pathways in FLT3 -ITD–mutated AML cells, leading to potent growth inhibition with IC 50 values of <1 nM. When quizartinib was administered to mice bearing FLT3 -ITD mutated tumors, AC886 was rapidly detected and tumor regression was observed at doses of ≥1 mg/kg without severe body weight loss. In addition, quizartinib inhibited the viability of midostaurin-resistant MOLM-14 cells and exerted potent antitumor activity in mouse xenograft models without severe body weight loss, while midostaurin and gilteritinib did not show significant antitumor effects. This is the first detailed characterization of quizartinib and AC886 in comparison with other FLT3 inhibitors under the same experimental conditions. Preclinical antileukemic activity in midostaurin-resistant FLT3 -ITD–mutated AML cells suggests the potential value of quizartinib following midostaurin failure in patients with FLT3 -ITD mutated AML.