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Ref Type Journal Article
PMID (18024392)
Authors Gleixner KV, Mayerhofer M, Sonneck K, Gruze A, Samorapoompichit P, Baumgartner C, Lee FY, Aichberger KJ, Manley PW, Fabbro D, Pickl WF, Sillaber C, Valent P
Title Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT.
Journal Haematologica
Vol 92
Issue 11
Date 2007 Nov
URL
Abstract Text 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.We examined the effects of the novel TK-inhibitor dasatinib alone and in combination with other targeted drugs on growth of neoplastic MC.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.Combinations of targeted drugs may represent an interesting pharmacologic approach for the treatment of aggressive SM or MCL.

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Molecular Profile Treatment Approach
KIT D816V Dasatinib
KIT D816H Dasatinib
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560G KIT D816V mast-cell leukemia sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth and induced apoptosis in a mast-cell leukemia cell line harboring both KIT V560G and KIT D816V in culture (PMID: 18024392). 18024392