Reference Detail

Ref Type

Journal Article

PMID

(15256420)

Authors

Clark JJ, Cools J, Curley DP, Yu JC, Lokker NA, Giese NA, Gilliland DG

Title

Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood	104	9	2004 Nov 1	2867-72	Blood

URL

Abstract Text

FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in acute myeloid leukemia (AML). We tested the sensitivity of 8 activation loop mutations to the small molecule FLT3 inhibitor, MLN518. Each FLT3 activation loop mutant, including D835Y, D835A, D835E, D835H, D835N, D835V, D835del, and I836del, transformed Ba/F3 cells to factor-independent proliferation and had constitutive tyrosine kinase activation, as assessed by FLT3 autophosphorylation and activation of downstream effectors, including STAT5 and ERK. MLN518 inhibited FLT3 autophosphorylation and phosphorylation of STAT5 and ERK in FLT3-ITD-transformed Ba/F3 cells with an IC(50) (50% inhibition of cell viability) of approximately 500 nM. However, there was a broad spectrum of sensitivity among the 8 activation loop mutants, with IC(50) ranging from approximately 500 nM to more than 10 microM for the inhibition of phosphorylation of FLT3, STAT5, and ERK. The relative sensitivity of the mutants to MLN518 in biochemical assays correlated with the cellular IC(50) for cytokine-independent proliferation of FLT3-transformed Ba/F3 cells in the presence of MLN518. Thus, certain activation loop mutations in FLT3 simultaneously confer resistance to small molecule inhibitors. These findings have implications for the evaluation of responses in clinical trials with FLT3 inhibitors and provide a strategy to screen for compounds that can overcome resistance.

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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
FLT3	D835A	missense	gain of function	FLT3 D835A lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835A results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).
FLT3	D835del	deletion	gain of function	FLT3 D835del results in the deletion of an amino acid from the activation loop in the protein kinase domain of the Flt3 protein at amino acid 835 (PMID: 25837374). D835del results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).
FLT3	D835E	missense	gain of function	FLT3 D835E lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835E results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).
FLT3	D835H	missense	gain of function	FLT3 D835H lies within the protein kinase domain activation loop of the Flt3 protein (PMID: 11290608). D835H results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).
FLT3	D835N	missense	gain of function	FLT3 D835N lies within the protein kinase domain activation loop of the Flt3 protein (PMID: 11290608). D835N results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).
FLT3	D835V	missense	gain of function	FLT3 D835V lies within the protein kinase domain activation loop of the Flt3 protein (PMID: 11290608). D835V results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
FLT3	D835X	missense	unknown	FLT3 D835X indicates any Flt3 missense mutation that results in the replacement of the aspartic acid (D) at amino acid 835 by a different amino acid. FLT3 codon 835 mutations are hotspot mutations that often result in constitutive phosphorylation of Flt3 and activation of downstream signaling (PMID: 11290608, PMID: 15256420).
FLT3	D835Y	missense	gain of function	FLT3 D835Y lies within the protein kinase domain activation loop of the Flt3 protein (UniProt.org, PMID: 11290608). D835Y results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420, PMID: 30651561), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).	Y
FLT3	I836del	deletion	gain of function	FLT3 I836del results in the deletion of an amino acid in the protein kinase domain activation loop of the Flt3 protein at amino acid 836 (PMID: 12663439). I836del results in constitutive phosphorylation of Flt3 and activation of Stat5, Erk signaling, leading to transformation of cultured cells (PMID: 15256420).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 I836del	cancer	sensitive	Tandutinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tandutinib (CT53518) inhibited phosphorylation of FLT3 and activation of ERK and STAT5, and reduced growth of transformed cells expressing FLT3 I836del in culture (PMID: 15256420).	15256420