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Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

From the Department of Internal Medicine I, Division of Hematology & Hemostaseology (KVG, KS, CB, KJA, CS, PV); Institute of Immunology (AG, WFP), Clinical Institute of Medical and Chemical Laboratory Diagnostics (MM); Center of Anatomy and Cell Biology, Medical University of Vienna, Austria (PS); Oncology Drug Discovery, Bristol-Myers Squibb, Princeton, NJ, USA (FYL); Novartis Pharma AG, Basel, Switzerland (PWM, DF)

Correspondence: Peter Valent, MD, Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, AKH-Wien, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: peter.valent{at}meduniwien.ac.at

Background and Objectives: In a majority of all patients with systemic mastocytosis (SM) including those with mast cell leukemia (MCL), neoplastic mast cells (MC) display the D816V-mutated variant of KIT. The respective oncoprotein, KIT D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. Therefore, several attempts have been made to identify KIT D816V-targeting drugs.

Design and Methods: We examined the effects of the novel TK-inhibitor dasatinib alone and in combination with other targeted drugs on growth of neoplastic MC.

Results: Confirming previous studies, dasatinib was found to inhibit the TK activity of wild type (wt) KIT and KIT-D816V as well as growth and survival of neoplastic MC and of the MCL cell line, HMC-1. The growth-inhibitory effects of dasatinib in HMC-1 cells were found to be associated with a decrease in expression of CD2 and CD63. In addition, we found that dasatinib blocks KIT D816V-induced cluster-formation and viability in Ba/F3 cells. In drug combination experiments, dasatinib was found to co-operate with PKC412, AMN107, imatinib, and 2CdA in producing growth-inhibition and apoptosis in neoplastic MC. In HMC-1.1 cells lacking KIT D816V, all drug interactions were found to be synergistic in nature. By contrast, in HMC-1.2 cells exhibiting KIT D816V, only the combinations dasatinib+PKC412 and dasatinib+2CdA were found to produce synergistic effects.

Interpretation and Conclusions: Combinations of targeted drugs may represent an interesting pharmacologic approach for the treatment of aggressive SM or MCL.

Key words: mastocytosis, KIT D816V, apoptosis, targeted drugs, drug synergism.

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