Reference Detail

Ref Type

Journal Article

PMID

(16397263)

Authors

Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC

Title

Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	66	1	2006 Jan 01	473-81	Cancer Res

URL

Abstract Text

Activating mutations of the activation loop of KIT are associated with certain human neoplasms, including the majority of patients with systemic mast cell disorders, as well as cases of seminoma, acute myelogenous leukemia (AML), and gastrointestinal stromal tumors (GISTs). The small-molecule tyrosine kinase inhibitor imatinib mesylate is a potent inhibitor of wild-type (WT) KIT and certain mutant KIT isoforms and has become the standard of care for treating patients with metastatic GIST. However, KIT activation loop mutations involving codon D816 that are typically found in AML, systemic mastocytosis, and seminoma are insensitive to imatinib mesylate (IC50 > 5-10 micromol/L), and acquired KIT activation loop mutations can be associated with imatinib mesylate resistance in GIST. Dasatinib (formerly BMS-354825) is a small-molecule, ATP-competitive inhibitor of SRC and ABL tyrosine kinases with potency in the low nanomolar range. Some small-molecule SRC/ABL inhibitors also have potency against WT KIT kinase. Therefore, we hypothesized that dasatinib might inhibit the kinase activity of both WT and mutant KIT isoforms. We report herein that dasatinib potently inhibits WT KIT and juxtamembrane domain mutant KIT autophosphorylation and KIT-dependent activation of downstream pathways important for cell viability and cell survival, such as Ras/mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt, and Janus-activated kinase/signal transducers and activators of transcription. Furthermore, dasatinib is a potent inhibitor of imatinib-resistant KIT activation loop mutants and induces apoptosis in mast cell and leukemic cell lines expressing these mutations (potency against KIT D816Y >> D816F > D816V). Our studies suggest that dasatinib may have clinical efficacy against human neoplasms that are associated with gain-of-function KIT mutations.

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Molecular Profile	Treatment Approach

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
KIT	D816F	missense	gain of function	KIT D816F lies within the tyrosine kinase domain 2 of the Kit protein (PMID: 17555444). D816F results in constitutive phosphorylation of Kit and activation of Stat3, Mapk, and Akt signaling in cultured cells (PMID: 9990072, PMID: 16397263), and also confers resistance to imatinib in culture (PMID: 16397263).	Y
KIT	D816Y	missense	gain of function	KIT D816Y lies within the tyrosine kinase domain 2 of the Kit protein (PMID: 21640708). D816Y results in constitutive phosphorylation of Kit, activation of Akt and Mapk pathways in cultured cells (PMID: 21640708, PMID: 16397263), and confers resistance to imatinib in culture (PMID: 16397263).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT D816Y	Advanced Solid Tumor	resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT D816Y were resistant to Gleevec (imatinib mesylate) in culture (PMID: 16397263).	16397263
KIT V560D	Advanced Solid Tumor	sensitive	Dasatinib	Preclinical	Actionable	In a preclinical study, transformed cells expressing KIT V560D were sensitive to Sprycel (dasatinib) in culture (PMID: 16397263).	16397263
KIT D816F	Advanced Solid Tumor	resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT D816F were resistant to Gleevec (imatinib mesylate) in culture (PMID: 16397263).	16397263