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Chronic myeloproliferative neoplasms

Drug-induced inhibition of phosphorylation of STAT5 overrides drug resistance in neoplastic mast cells

Leukemia volume 32, pages 1016–1022 (2018)Cite this article

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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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Acknowledgements

This study was supported by Austrian Science Fund (FWF), SFB grants F4701-B20, F4704-B20, F4707-B20 and F4710-B20.

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Authors and Affiliations

  1. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria

    B Peter, G Eisenwort, K Blatt, H Herrmann, E Hadzijusufovic, W R Sperr & P Valent

  2. Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria

    B Peter, G Eisenwort, D Berger, G Stefanzl, K Blatt, E Hadzijusufovic, W R Sperr & P Valent

  3. Laboratoire de Biologie et Pharmacologie Appliquée, CNRS UMR 8113, Ecole Normale Superieure de Cachan, Cachan, France

    S Bibi & M Arock

  4. Ludwig Boltzmann Institute for Cancer Research, Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria

    B Wingelhofer & R Moriggl

  5. Department for Companion Animals and Horses, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria

    E Hadzijusufovic & M Willmann

  6. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    G Hoermann

  7. Research Institute of Molecular Pathology (IMP), Vienna, Austria

    T Hoffmann & J Zuber

  8. Department of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    J Schwaab, M Jawhar & A Reiter

  9. University Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria

    K Sotlar

  10. Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany

    H-P Horny

  11. Laboratory of Hematology, Pitié-Salpêtrière Hospital, Paris, France

    M Arock

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  1. B Peter
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Correspondence to P Valent.

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Competing interests

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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