All-trans retinoic acid potentiates cell death induced by quizartinib in acute myeloid leukemia with FLT3-ITD mutations

Abstract

Acute myeloid leukemia (AML) with FLT3-ITD mutation represents a quarter of AML patients and is associated with high relapse rate and dismal prognosis. FLT3 tyrosine kinase inhibitors (TKIs) were developed in order to target this genetic alteration and among these TKIs, AC220 (quizartinib) combined with chemotherapy has already shown an increased overall survival for patients with AML with FLT3-ITD mutation. Even though this increase in overall survival was significant, it remains discrete, and relapse rate is still high, so there is an unmet medical need. All-trans retinoic acid (ATRA) is well known for its effectiveness in acute promyelocytic leukemia (APL) treatment and has already been shown to have synergistic effects combined with another TKI, sorafenib. In this study, quizartinib, a more potent FLT3-TKI, was tested in combination with ATRA in the AML FLT3-ITD positive cell lines MOLM-13 and MV4-11. ATRA has effectively improved AC220 induced cell death via caspase activation. In addition, ATRA in combination with AC220 treatment notably enhanced BECN1 cleavage compared to AC220 treatment alone. Finally, in a xenotransplantation model ATRA plus AC220 was more efficient to reduce the leukemic burden than monotherapy with ATRA or AC220. Taken together, our results are a proof of the concept that ATRA and AC220 have synergistic anti-leukemic effects.

Keywords: AC220; ATRA; Acute myeloid leukemia; All-trans retinoic acid; Autophagy; FLT3-ITD; FLT3-TKIs; Quizartinib.