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Ferrata Storti Foundation
Acute Myeloid Leukemia
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
Haematologica 2018 Volume 103(10):1642-1653
Shacham,2 Naval Daver3 and Michael Andreeff1,3
Weiguo Zhang,1 Charlie Ly,1 Jo Ishizawa,1 Hong Mu,1 Vivian Ruvolo,1 Sharon
1
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of
Texas MD Anderson Cancer Center, Houston, TX; 2Karyopharm Therapeutics Inc., Newton, MA and 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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 activa- tion 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 muta- tions. 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 trig- gered 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 selinex- or/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.
Introduction
Acute myeloid leukemia (AML) is a molecularly heterogeneous hematologic dis- ease defined by the accumulation of immature myeloid cells in blood and bone marrow, which results from a dysregulation of normal proliferation, differentiation, and apoptosis in these cells.1 Mutations of the fms-like tyrosine kinase-3 (FLT3) gene, including internal tandem duplication (ITD) and the tyrosine kinase domain (TKD) mutations, are common in patients with AML with approximately one-third of newly diagnosed AML patients carrying these mutations. These gain-of-function
Correspondence:
mandreef@mdanderson.org
Received: November 20, 2017. Accepted: May 16, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2017.185082
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1642
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