SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase

被引:151
作者
Yee, KWH
O'Farrell, AM
Smolich, BD
Cherrington, JM
McMahon, G
Wait, CL
McGreevey, LS
Griffith, DJ
Heinrich, MC
机构
[1] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Dept Med, Portland, OR USA
[2] SUGEN, San Francisco, CA USA
关键词
D O I
10.1182/blood-2002-02-0531
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the type III RTK family. Given the conserved homology between members of this family, we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC50], 100 nM; and SU5614 IC50 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC50, 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines. Treatment of these cells with an alternative growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.
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页码:2941 / 2949
页数:9
相关论文
共 60 条
[1]   FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group [J].
Abu-Duhier, FM ;
Goodeve, AC ;
Wilson, GA ;
Gari, MA ;
Peake, IR ;
Rees, DC ;
Vandenberghe, EA ;
Winship, PR ;
Reilly, JT .
BRITISH JOURNAL OF HAEMATOLOGY, 2000, 111 (01) :190-195
[2]  
Advani SH, 1999, AM J HEMATOL, V60, P87, DOI 10.1002/(SICI)1096-8652(199902)60:2<87::AID-AJH1>3.0.CO
[3]  
2-5
[4]   GENOMIC STRUCTURE OF THE DOWNSTREAM PART OF THE HUMAN FLT3 GENE - EXON/INTRON STRUCTURE CONSERVATION AMONG GENES ENCODING RECEPTOR TYROSINE KINASES (RTK) OF SUBCLASS-III [J].
AGNES, F ;
SHAMOON, B ;
DINA, C ;
ROSNET, O ;
BIRNBAUM, D ;
GALIBERT, F .
GENE, 1994, 145 (02) :283-288
[5]  
ANDRE C, 1992, ONCOGENE, V7, P685
[6]  
Baldwin BR, 2001, BLOOD, V98, p801A
[7]   Phosphatidylinositol-3' kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase [J].
Beslu, N ;
LaRose, J ;
Casteran, N ;
Birnbaum, D ;
Lecoq, E ;
Dubreuil, P ;
Rottapel, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (33) :20075-20081
[8]   A NEW ACUTE TRANSFORMING FELINE RETROVIRUS AND RELATIONSHIP OF ITS ONCOGENE V-KIT WITH THE PROTEIN-KINASE GENE FAMILY [J].
BESMER, P ;
MURPHY, JE ;
GEORGE, PC ;
QIU, F ;
BERGOLD, PJ ;
LEDERMAN, L ;
SNYDER, HW ;
BRODEUR, D ;
ZUCKERMAN, EE ;
HARDY, WD .
NATURE, 1986, 320 (6061) :415-421
[9]   Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts [J].
Birkenkamp, KU ;
Geugien, M ;
Lemmink, HH ;
Kruijer, W ;
Vellenga, E .
LEUKEMIA, 2001, 15 (12) :1923-1931
[10]   Superiority of Denaturing High Performance Liquid Chromatography over single-stranded conformation and conformation-sensitive gel electrophoresis for mutation detection in TSC2 [J].
Choy, YS ;
Dabora, SL ;
Hall, F ;
Ramesh, V ;
Niida, Y ;
Franz, D ;
Kasprzyk-Obara, J ;
Reeve, MP ;
Kwiatkowski, DJ .
ANNALS OF HUMAN GENETICS, 1999, 63 :383-391