Oncotarget

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Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase

Ellen L. Weisberg _, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J. Buhrlage, Jing Yang, Paul W. Manley, Chengcheng Meng, Michael Buonopane, John F. Daley, Suzan Lazo, Renee Wright, David M. Weinstock, Amanda L. Christie, Kimberly Stegmaier and James D. Griffin

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Oncotarget. 2017; 8:52026-52044. https://doi.org/10.18632/oncotarget.19036

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Abstract

Ellen L. Weisberg1,6, Alexandre Puissant2,6, Richard Stone1,6, Martin Sattler1,6, Sara J. Buhrlage3,4,6, Jing Yang3,6, Paul W. Manley5, Chengcheng Meng1, Michael Buonopane1, John F. Daley1, Suzan Lazo1, Renee Wright1, David M. Weinstock1,6, Amanda L. Christie1, Kimberly Stegmaier2,6 and James D. Griffin1,6

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

4 Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts, USA

5 Novartis Institutes of Biomedical Research, Basel, Switzerland

6 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

Correspondence to:

Ellen L. Weisberg, email:

James D. Griffin, email:

Keywords: acute myelogenous leukemia, midostaurin, R406, R788, FLT3-ITD

Received: March 16, 2017 Accepted: May 12, 2017 Published: July 06, 2017

Abstract

Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI). Up to now, the activity of the multi-targeted FLT3 inhibitor, midostaurin, against cells expressing activated SYK has not been explored in the context of leukemia, although SYK has been identified as a target of midostaurin in systemic mastocytosis. We compared the ability of midostaurin to inhibit activated SYK in mutant FLT3-positive AML cells with that of inhibitors displaying dual SYK/FLT3 inhibition, targeted SYK inhibition, and targeted FLT3 inhibition. Our findings suggest that dual FLT3/SYK inhibitors and FLT3-targeted drugs potently kill oncogenic FLT3-transformed cells, while SYK-targeted small molecule inhibition displays minimal activity. However, midostaurin and other dual FLT3/SYK inhibitors display superior anti-proliferative activity when compared to targeted FLT3 inhibitors, such as crenolanib and quizartinib, against cells co-expressing FLT3-ITD and constitutively activated SYK-TEL. Interestingly, additional SYK suppression potentiated the effects of dual FLT3/SYK inhibitors and targeted FLT3 inhibitors against FLT3-ITD-driven leukemia, both in the absence and presence of activated SYK. Taken together, our findings have important implications for the design of drug combination studies in mutant FLT3-positive patients and for the design of future generations of FLT3 inhibitors.


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