The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis
Mathias Schneeweiss,
Barbara Peter,
Siham Bibi,
Gregor Eisenwort,
Dubravka Smiljkovic,
Katharina Blatt,
Mohamad Jawhar,
Daniela Berger,
Gabriele Stefanzl,
Susanne Herndlhofer,
Georg Greiner,
Gregor Hoermann,
Emir Hadzijusufovic,
Karoline V. Gleixner,
Peter Bettelheim,
Klaus Geissler,
Wolfgang R. Sperr,
Andreas Reiter,
Michel Arock,
Peter Valent
Affiliations
Mathias Schneeweiss
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Barbara Peter
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Siham Bibi
Laboratoire de Biologie et Pharmacologie Appliquee, CNRS UMR 8113, Ecole Normale Superieure de Cachan, France
Gregor Eisenwort
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Dubravka Smiljkovic
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria
Katharina Blatt
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Mohamad Jawhar
Department of Hematology and Oncology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Germany
Daniela Berger
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Gabriele Stefanzl
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Susanne Herndlhofer
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Georg Greiner
Department of Laboratory Medicine, Medical University of Vienna, Austria
Gregor Hoermann
Department of Laboratory Medicine, Medical University of Vienna, Austria
Emir Hadzijusufovic
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria;Department for Companion Animals and Horses, University Clinic for Small Animals, Internal Medicine Small Animals, University of Veterinary Medicine Vienna, Austria
Karoline V. Gleixner
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Peter Bettelheim
Elisabethinen Hospital Linz, Austria
Klaus Geissler
Fifth Medical Department, Hospital Hietzing, Vienna, Austria
Wolfgang R. Sperr
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
Andreas Reiter
Department of Hematology and Oncology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Germany
Michel Arock
Laboratoire de Biologie et Pharmacologie Appliquee, CNRS UMR 8113, Ecole Normale Superieure de Cachan, France
Peter Valent
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
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 confers resistance against imatinib. Clinical problems in systemic mastocytosis 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 (IC50
