The growth-inhibitory effects of dasatinib in HMC-1 cells were found to be associated with a decrease in expression of CD2 and CD63. 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. 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. Therefore, several attempts have been made to identify KIT D816V-targeting drugs. The respective oncoprotein, KIT D816V, exhibits constitutive tyrosine kinase (TK) activity and has been implicated in malignant cell growth. RVT was an employee and is a shareholder of Eli Lilly and Company, and is currently employed by Astellas Pharma.Abstract 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. SVB is an employee and shareholder of Eli Lilly and Company. He is an Ad Hoc Consultant and on the Steering Committee and Data Safety and Monitoring Board for Celgene. He is on the Data Safety and Monitoring Board for the following companies: Argenx, Celgene, and Takeda. He is on the Advisory Board of the following companies: Actinium, Amgen, Astellas, and Macrogenics. He does Ad Hoc consulting for the following companies: Astrazeneca, Cornerstone, Jazz, Daiichi-Sankyo, Otsuka/Astex, Pfizer, and Stemline. RS does Ad Hoc consulting for and receives clinical research support to Dana-Farber Cancer Institute from the following companies: Abbvie, Agios, Arog, and Novartis. EW has received a royalty payment from Novartis Pharmaceuticals. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. N is a founder, science advisory board member (SAB), and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. JDG receives funding and has received a royalty payment from Novartis Pharmaceuticals and receives funding from Eli Lilly and Company. ERK implication in cell cycle regulation. 2017 8:67639–50.Ĭhambard JC, Lefloch R, Pouyssegur J, Lenormand P. Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming. 2003 3:173–83.īhanot H, Weisberg EL, Reddy MM, Nonami A, Neuberg D, Stone RM, et al. Validation of a therapeutic target identified by gene expression based classification. 2005 7:129–41.Īrmstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al.
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