Work

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

Year: 2017

Type: article

Abstract: // Ellen L. Weisberg 1,6 , Alexandre Puissant 2,6 , Richard Stone 1,6 , Martin Sattler 1,6 , Sara J. Buhrlage 3,4,6 , Jing Yang 3,6 , Paul W. Manley 5 , Chengcheng Meng 1 , Michael Buonopane 1 , John F. Daley 1 , Suzan Lazo 1 , Renee Wright 1 , David M. Weinstock 1,6 , Amanda L. Christie 1 , Kimberly Stegmaier 2,6 and James D. Griffin 1,6 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.19036