Abstract
Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5–50 nM), HMC-1.2 (IC50 1–10 nM), ROSAKIT WT (IC50 1–10 nM), ROSAKIT D816V (IC50 50–500 nM) and MCPV-1.1 (IC50 100–1000 nM). Moreover, R763 induced growth inhibition in primary neoplastic MC in patients with ASM and MCL. Growth-inhibitory effects of R763 were accompanied by signs of apoptosis and a G2/M cell cycle arrest. R763 also inhibited phosphorylation of KIT, BTK, AKT and STAT5 in neoplastic MC. The most sensitive target appeared to be STAT5. In fact, tyrosine phosphorylation of STAT5 was inhibited by R763 at 10 nM. At this low concentration, R763 produced synergistic growth-inhibitory effects on neoplastic MC when combined with midostaurin or dasatinib. Together, R763 is a novel promising multi-kinase inhibitor that blocks STAT5 activation and thereby overrides drug-resistance in neoplastic MC.
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This study was supported by Austrian Science Fund (FWF), SFB grants F4701-B20, F4704-B20, F4707-B20 and F4710-B20.
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GH received honoraria from Novartis and Ariad. WRS received honoraria from Novartis and Celgene, and a research grant from Lipomed. PV, H-PH and AR served as a Consultant in a global Novartis trial examining the effects of midostaurin in advanced SM. JZ received institutional support from Boehringer-Ingelheim, and is consultant and stock holder at Mirimus Inc. AR received a research grant from Novartis, honoraria from Novartis and BMS, and served in advisory boards organized by Novartis. MA received research grants from Blueprint and Deciphera, and received honoraria from Deciphera. PV received research grants from Novartis, Blueprint and Deciphera, and honoraria from Novartis, Celgene, Pfizer and Deciphera. The remaining authors declare no conflicts of interest.
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Peter, B., Bibi, S., Eisenwort, G. et al. Drug-induced inhibition of phosphorylation of STAT5 overrides drug resistance in neoplastic mast cells. Leukemia 32, 1016–1022 (2018). https://doi.org/10.1038/leu.2017.338
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DOI: https://doi.org/10.1038/leu.2017.338
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