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Ref Type Journal Article
PMID (25231999)
Authors Konig H, Levis M
Title Targeting FLT3 to treat leukemia.
URL
Abstract Text Approximately 23% of acute myeloid leukemia (AML) patients younger than 60 years of age carry a mutation in the transmembrane domain of the FMS-like tyrosine kinase-3 (FLT3) gene (FLT3/internal tandem duplications [ITD]). In normal karyotype AML, the presence of a FLT3/ITD mutation is associated with poor prognosis, as mirrored by a high risk of relapse even after allogeneic stem cell transplantation. The poor prognostic impact along with the observation that FLT3 is frequently overexpressed in the majority of AML cases has formed the platform for the development of FLT3-targeted strategies. To date, several FLT3 kinase inhibitors have been investigated in preclinical and clinical studies. However, as of yet, none of the studied FLT3 inhibitors has received FDA approval for routine clinical use in AML. This is in part due to the 'off target' effects observed with most inhibitors when administered at concentrations needed to achieve sustained levels of FLT3 inhibition, which are required to exhibit substantial cytotoxic effects against leukemic blasts. Furthermore, the development of resistance mutations has emerged as a clinical issue posing a threat to successful FLT3 inhibitor therapy.In this review, the authors provide a brief summary of FLT3 inhibitors investigated thus far, and discuss current treatment approaches and strategies how to best incorporate FLT3 tyrosine kinase inhibitors (TKIs) into therapy.The combination of a FLT3 inhibitor with conventional chemotherapeutic regimens, epigenetic modifiers or inhibitors of FLT3 downstream and collateral effectors has emerged as a promising strategy to improve treatment outcome. The future of a tailored, molecular-based treatment approach for FLT3-mutated AML demands novel clinical trial concepts based on harmonized and aligned research goals between clinical and research centers and industry.

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Molecular Profile Treatment Approach
FLT3 Y597_E598insDEYFYVDFREY FLT3 Inhibitor
FLT3 F594Y FLT3 Inhibitor
FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL FLT3 Inhibitor
FLT3 F590_F605dup FLT3 Inhibitor
FLT3 act mut FLT3 Inhibitor
FLT3 S840_N841insGS FLT3 Inhibitor
FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE FLT3 Inhibitor
FLT3 V592A FLT3 Inhibitor
FLT3 F590_D593delinsLY FLT3 Inhibitor
FLT3 V579A FLT3 Inhibitor
FLT3 A680V FLT3 Inhibitor
FLT3 E598_Y599insDVDFREYE FLT3 Inhibitor
FLT3 W603_E604insDREYEYDLKW FLT3 Inhibitor
FLT3 R834Q FLT3 Inhibitor
FLT3 D835Y FLT3 Inhibitor
FLT3 D593_D600dup FLT3 Inhibitor
FLT3 D835N FLT3 Inhibitor
FLT3 L601_K602insNVDFREYEYDL FLT3 Inhibitor
FLT3 F612_G613insQGFYVDFREYEYDLKWEFPRENLEF FLT3 Inhibitor
FLT3 Y599_D600insPAPQIMSTSTLISENMNIA FLT3 Inhibitor
FLT3 E598_Y599insVAYVDFREYE FLT3 Inhibitor
FLT3 N676K FLT3 Inhibitor
FLT3 over exp FLT3 Inhibitor
FLT3 Y599_D600insGLYVDFREYEY FLT3 Inhibitor
FLT3 I836D FLT3 Inhibitor
FLT3 D839G FLT3 Inhibitor
FLT3 E604_F605insSPRGGNEYFYVDFREYEYDLKWE FLT3 Inhibitor
FLT3 I836L FLT3 Inhibitor
FLT3 Y597_K602dup FLT3 Inhibitor
FLT3 Q575del FLT3 Inhibitor
FLT3 D835E FLT3 Inhibitor
FLT3 I836del FLT3 Inhibitor
FLT3 G846S FLT3 Inhibitor
FLT3 S451F FLT3 Inhibitor
FLT3 D835K FLT3 Inhibitor
FLT3 S941_F942insRVS FLT3 Inhibitor
FLT3 exon 14 ins FLT3 Inhibitor
FLT3 S585_F594dup FLT3 Inhibitor
FLT3 L576R FLT3 Inhibitor
FLT3 S584_F605dup FLT3 Inhibitor
FLT3 I836S FLT3 Inhibitor
FLT3 V592G FLT3 Inhibitor
FLT3 N841I FLT3 Inhibitor
FLT3 D835del FLT3 Inhibitor
FLT3 E598_Y599insSGSSDNEYFYVDFREYE FLT3 Inhibitor
FLT3 R595_L601dup FLT3 Inhibitor
FLT3 S584_D600dup FLT3 Inhibitor
FLT3 S574del FLT3 Inhibitor
FLT3 Y572del FLT3 Inhibitor
FLT3 D835L FLT3 Inhibitor
FLT3 Y842H FLT3 Inhibitor
FLT3 I867S FLT3 Inhibitor
FLT3 D835V FLT3 Inhibitor
FLT3 G613_K614insYVDFREYEYDLKWEFRPRENLEFG FLT3 Inhibitor
FLT3 M578_E598dup FLT3 Inhibitor
FLT3 F590_Y591delinsGD FLT3 Inhibitor
FLT3 F594C FLT3 Inhibitor
FLT3 F594_D600dup FLT3 Inhibitor
FLT3 E598_Y599del FLT3 Inhibitor
FLT3 K614_G617del FLT3 Inhibitor
FLT3 D835A FLT3 Inhibitor
FLT3 Y842C FLT3 Inhibitor
FLT3 E598_F612dup FLT3 Inhibitor
FLT3 F594L FLT3 Inhibitor
FLT3 I836T FLT3 Inhibitor
FLT3 K663Q FLT3 Inhibitor
FLT3 R595_E596insDYVDFR FLT3 Inhibitor
FLT3 N587_D600dup FLT3 Inhibitor
FLT3 D835G FLT3 Inhibitor
FLT3 Y599_D600insEYEYEYEY FLT3 Inhibitor
FLT3 Y599_E604dup FLT3 Inhibitor
FLT3 Y599_D600insSTDNEYFYVDFREYEY FLT3 Inhibitor
FLT3 D835X FLT3 Inhibitor
FLT3 D586_E596dup FLT3 Inhibitor
FLT3 E573del FLT3 Inhibitor
FLT3 Y572C FLT3 Inhibitor
FLT3 D835H FLT3 Inhibitor
FLT3 Y597_E598insAGSSDNEYFYVDFREY FLT3 Inhibitor
FLT3 F594_R595insGTGSSDNEYFYVDF FLT3 Inhibitor
FLT3 amp FLT3 Inhibitor
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