Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial
EHA Library. Zhang W. Oct 1, 2018; 234243 Topic: 2B Acute myeloid leukemia (AML) and leukemias of ambiguous lineage
Weiguo Zhang
Weiguo Zhang
Contributions
Journal Abstract

Co-Authors: Charlie Ly, Jo Ishizawa, Hong Mu, Vivian Ruvolo, Sharon Shacham, Naval Daver, Michael Andreeff

Abstract: Targeted therapies against FLT3-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (e.g., XPO1) and FLT3 concomitantly may be therapeutically effective. Here we report on the combinatorial inhibition of XPO1 using selinexor and FLT3 using sorafenib. Selinexor exerted marked cell killing of human and murine FLT3-mutant acute myeloid leukemia cells, including those harboring internal tandem duplication and/or tyrosine kinase domain point mutations. Interestingly, selinexor treatment of murine FLT3-mutant acute myeloid leukemia cells activated FLT3 and its downstream MAPK or AKT signaling pathways. When combined with sorafenib, selinexor triggered marked synergistic pro-apoptotic effects. This was preceded by elevated nuclear levels of ERK, AKT, NFκB, and FOXO3a. Five days of in vitro combination treatment using low doses (i.e., 5 to 10 nM) of each agent promoted early myeloid differentiation of MOLM13 and MOLM14 cells without noticeable cell killing. The combinatorial therapy demonstrated profound in vivo anti-leukemia efficacy in a human FLT3-mutated xenograft model. In an ongoing phase IB clinical trial the selinexor/sorafenib combination induced complete/partial remissions in six of 14 patients with refractory acute myeloid leukemia, who had received a median of three prior therapies (ClinicalTrials.gov: NCT02530476). These results provide pre-clinical and clinical evidence for an effective combinatorial treatment strategy targeting XPO1 and FLT3 in FLT3- mutated acute myeloid leukemias.

Article Number: 1642

Doi: 10.3324/haematol.2017.185082

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