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Myeloproliferative Disorders
The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival
of multiple neoplastic cell types in advanced mastocytosis
Ferrata Storti Foundation
Mathias Schneeweiss,1,2 Barbara Peter,1,2 Siham Bibi,3 Gregor Eisenwort,1,2 Dubravka Smiljkovic,1 Katharina Blatt,1,2 Mohamad Jawhar,4 Daniela Berger,2 Gabriele Stefanzl,2 Susanne Herndlhofer,1,2 Georg Greiner,5 Gregor Hoermann,5 Emir Hadzijusufovic,1,2,6 Karoline V. Gleixner,1,2 Peter Bettelheim,7 Klaus Geissler,8 Wolfgang R. Sperr,1,2 Andreas Reiter,4 Michel Arock3 and Peter Valent1,2
Haematologica 2018 Volume 103(5):799-809
1Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria; 2Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; 3Laboratoire de Biologie et Pharmacologie Appliquee, CNRS UMR 8113, Ecole Normale Superieure de Cachan, France; 4Department of Hematology and Oncology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Germany; 5Department of Laboratory Medicine, Medical University of Vienna, Austria; 6Department for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine Vienna, Austria; 7Elisabethinen Hospital Linz, Austria and 8Fifth Medical Department, Hospital Hietzing, Vienna, Austria
ABSTRACT
Systemic mastocytosis is a complex disease defined by abnormal growth and accumulation of neoplastic mast cells in various organs. Most patients exhibit a D816V-mutated variant of KIT, which con- fers resistance against imatinib. Clinical problems in systemic mastocyto- sis arise from mediator-related symptoms and/or organ destruction caused by malignant expansion of neoplastic mast cells and/or other myeloid cells in various organ systems. DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis. We found that DCC-2618 inhibits the proliferation and survival of various human mast cell lines (HMC-1, ROSA, MCPV-1) as well as primary neoplastic mast cells obtained from patients with advanced systemic mastocytosis (IC
50 <1 μM). Moreover, DCC-2618 decreased growth and survival of primary neoplastic eosinophils obtained from patients with systemic mastocyto- sis or eosinophilic leukemia, leukemic monocytes obtained from patients with chronic myelomonocytic leukemia with or without concomitant systemic mastocytosis, and blast cells obtained from patients with acute myeloid leukemia. Furthermore, DCC-2618 was found to suppress the proliferation of endothelial cells, suggesting additional drug effects on systemic mastocytosis-related angiogenesis. Finally, DCC-2618 was found to downregulate IgE-mediated histamine release from basophils and tryptase release from mast cells. Together, DCC-2618 inhibits growth, survival and activation of multiple cell types relevant to advanced systemic mastocytosis. Whether DCC-2618 is effective in vivo in patients with advanced systemic mastocytosis is currently under inves-
tigation in clinical trials.
Introduction
Systemic mastocytosis (SM) is a hematopoietic neoplasm with complex biology and pathology, and a variable clinical course.1-7 The disease is characterized by abnormal expansion and accumulation of neoplastic mast cells (MC) in one or more
Correspondence:
peter.valent@meduniwien.ac.at
Received: September 1, 2017. Accepted: January 31, 2018. Pre-published: February 8, 2018.
doi:10.3324/haematol.2017.179895
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/799
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Haematologica | 2018; 103(5)
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