@article{Weiguo Zhang_Charlie Ly_Jo Ishizawa_Hong Mu_Vivian Ruvolo_Sharon Shacham_Naval Daver_Michael Andreeff_2018, place={Pavia, Italy}, title={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}, volume={103}, url={https://haematologica.org/article/view/8621}, DOI={10.3324/haematol.2017.185082}, abstractNote={Targeted therapies against <em>FLT3</em>-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in <em>FLT3</em> 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 <em>FLT3</em>-mutant acute myeloid leukemia cells, including those harboring internal tandem duplication and/or tyrosine kinase domain point mutations. Interestingly, selinexor treatment of murine <em>FLT3</em>-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 <em>in vitro</em> 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 <em>in vivo</em> anti-leukemia efficacy in a human <em>FLT3</em>-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 (<a href="http://ClinicalTrials.gov">ClinicalTrials.gov</a>: <a class="external-ref external-ref-type-clintrialgov" href="/lookup/external-ref?link_type=CLINTRIALGOV&amp;access_num=NCT02530476&amp;atom=%2Fhaematol%2F103%2F10%2F1642.atom">NCT02530476</a>). These results provide pre-clinical and clinical evidence for an effective combinatorial treatment strategy targeting XPO1 and FLT3 in <em>FLT3</em&gt;- mutated acute myeloid leukemias.}, number={10}, journal={Haematologica}, author={Weiguo Zhang and Charlie Ly and Jo Ishizawa and Hong Mu and Vivian Ruvolo and Sharon Shacham and Naval Daver and Michael Andreeff}, year={2018}, month={Sep.}, pages={1642-1653} }