Preclinical characterization of quizartinib and AC886, a metabolite of quizartinib, in AML models, and anti-leukemic activity of quizartinib on midostaurin-resistant AML cells

FLT3 mutations have been found in about 30% of acute myeloid leukemia (AML) cases, and the most common form of FLT3 mutation is internal tandem duplication (ITD) in the juxtamembrane domain, which occurs in approximately 25% of adult AML patients and 10-15% of pediatric patients. FLT3-ITD is a driver mutation in AML and the FLT3-ITD presence is associated with poor prognosis in AML patients. Quizartinib is a second-generation small-molecule inhibitor of FLT3, and a phase 3, QuANTUM-R trial showed significantly prolonged overall survival in patients with FLT3-ITD-mutated relapsed/refractory AML. In this preclinical study, we characterized quizartinib and AC886, a metabolite of quizartinib, compared with other FLT3 inhibitors including midostaurin, gilteritinib, crenolanib and sorafenib, and then evaluated the anti-tumor effect of quizartinib on midostaurin-resistant AML cells. Selectivity profiling of the FLT3 inhibitors against over 400 kinases and over 80 non-kinases showed that quizartinib and AC886 were highly selective against FLT3. Quizartinib and AC886 clearly inhibited FLT3 signaling pathways such as STAT5, RAS/MAPK and PI3K/AKT cascades in FLT3-ITD-mutated AML cells, leading to potent growth inhibition of the AML cells with the IC50 values of Citation Format: Tomoya Aikawa, Noriko Togashi, Koichi Iwanaga, Hiroyuki Okada, Yumi Nishiya, Shinichi Inoue, Mark J. Levis, Takeshi Isoyama. Preclinical characterization of quizartinib and AC886, a metabolite of quizartinib, in AML models, and anti-leukemic activity of quizartinib on midostaurin-resistant AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1318.