|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 925-932
Inhibition of c-kit receptor tyrosine kinase activity by STI
571, a selective tyrosine kinase inhibitor
Michael C. Heinrich,
Diana J. Griffith,
Brian J. Druker,
Cecily L. Wait,
Kristen A. Ott, and
Amy J. Zigler
From the Division of Hematology and Medical Oncology, Department of
Medicine, Oregon Health Sciences University, and Portland Veterans
Affairs Medical Center, Portland, OR.
STI 571 (formerly known as CGP 57148B) is a known inhibitor of the
c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR)
tyrosine kinases. This compound is being evaluated in clinical trials
for the treatment of chronic myelogenous leukemia. We sought to extend
the activity profile of STI 571 by testing its ability to inhibit the
tyrosine kinase activity of c-kit, a receptor structurally similar to
PDGFR. We treated a c-kit expressing a human myeloid leukemia cell
line, M-07e, with STI 571 before stimulation with Steel factor (SLF).
STI 571 inhibited c-kit autophosphorylation, activation of
mitogen-activated protein (MAP) kinase, and activation of Akt without
altering total protein levels of c-kit, MAP kinase, or Akt. The
concentration that produced 50% inhibition for these effects was
approximately 100 nmol/L. STI 571 also significantly decreased
SLF-dependent growth of M-07e cells in a dose-dependent manner and
blocked the antiapoptotic activity of SLF. In contrast, the compound
had no effect on MAP kinase activation or cellular proliferation in
response to granulocyte-macrophage colony-stimulating factor. We also
tested the activity of STI 571 in a human mast cell leukemia cell line
(HMC-1), which has an activated mutant form of c-kit. STI 571 had a
more potent inhibitory effect on the kinase activity of this mutant
receptor than it did on ligand-dependent activation of the wild-type
receptor. These findings show that STI 571 selectively inhibits c-kit
tyrosine kinase activity and downstream activation of target proteins
involved in cellular proliferation and survival. This compound may be
useful in treating cancers associated with increased c-kit kinase activity.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. S.M. Smalley, R. Contractor, T. K. Nguyen, M. Xiao, R. Edwards, V. Muthusamy, A. J. King, K. T. Flaherty, M. Bosenberg, M. Herlyn, et al.
Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression
Cancer Res.,
July 15, 2008;
68(14):
5743 - 5752.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Schilder, M. W. Sill, R. B. Lee, T. J. Shaw, M. K. Senterman, A. J. Klein-Szanto, Z. Miner, and B. C. Vanderhyden
Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study
J. Clin. Oncol.,
July 10, 2008;
26(20):
3418 - 3425.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. I. Cancino, E. M. Toledo, N. R. Leal, D. E. Hernandez, L. F. Yevenes, N. C. Inestrosa, and A. R. Alvarez
STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer's {beta}-amyloid deposits
Brain,
June 17, 2008;
(2008)
awn125v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Tarn, L. Rink, E. Merkel, D. Flieder, H. Pathak, D. Koumbi, J. R. Testa, B. Eisenberg, M. von Mehren, and A. K. Godwin
Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors
PNAS,
June 17, 2008;
105(24):
8387 - 8392.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Puissant, S. Grosso, A. Jacquel, N. Belhacene, P. Colosetti, J.-P. Cassuto, and P. Auberger
Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol
FASEB J,
June 1, 2008;
22(6):
1894 - 1904.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al.
Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases
Clin. Cancer Res.,
May 1, 2008;
14(9):
2717 - 2725.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Boehrer, L. Ades, T. Braun, L. Galluzzi, J. Grosjean, C. Fabre, G. Le Roux, C. Gardin, A. Martin, S. de Botton, et al.
Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study
Blood,
February 15, 2008;
111(4):
2170 - 2180.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Ramanathan, M. J. Egorin, C. H.M. Takimoto, S. C. Remick, J. H. Doroshow, P. A. LoRusso, D. L. Mulkerin, J. L. Grem, A. Hamilton, A. J. Murgo, et al.
Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
J. Clin. Oncol.,
February 1, 2008;
26(4):
563 - 569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Gibbons, M. J. Egorin, R. K. Ramanathan, P. Fu, D. L. Mulkerin, S. Shibata, C. H.M. Takimoto, S. Mani, P. A. LoRusso, J. L. Grem, et al.
Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group
J. Clin. Oncol.,
February 1, 2008;
26(4):
570 - 576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Blanke, G. D. Demetri, M. von Mehren, M. C. Heinrich, B. Eisenberg, J. A. Fletcher, C. L. Corless, C. D.M. Fletcher, P. J. Roberts, D. Heinz, et al.
Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT
J. Clin. Oncol.,
February 1, 2008;
26(4):
620 - 625.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. D. Blanke, C. Rankin, G. D. Demetri, C. W. Ryan, M. von Mehren, R. S. Benjamin, A. K. Raymond, V. H.C. Bramwell, L. H. Baker, R. G. Maki, et al.
Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate At Two Dose Levels in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing the Kit Receptor Tyrosine Kinase: S0033
J. Clin. Oncol.,
February 1, 2008;
26(4):
626 - 632.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Jensen, M. A. Beaven, S. Iwaki, D. D. Metcalfe, and A. M. Gilfillan
Concurrent Inhibition of Kit- and Fc{epsilon}RI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation
J. Pharmacol. Exp. Ther.,
January 1, 2008;
324(1):
128 - 138.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Boss, R. V. Olmos, M. Sinaasappel, J. H. Beijnen, and J. H. M. Schellens
Application of PET/CT in the Development of Novel Anticancer Drugs
Oncologist,
January 1, 2008;
13(1):
25 - 38.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Desai, S. Shankar, M. C. Heinrich, J. A. Fletcher, C. D. Fletcher, J. Manola, J. A. Morgan, C. L. Corless, S. George, K. Tuncali, et al.
Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors
Clin. Cancer Res.,
September 15, 2007;
13(18):
5398 - 5405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jahn, E. Leifheit, S. Gooch, S. Sindhu, and K. Weinberg
Lipid rafts are required for Kit survival and proliferation signals
Blood,
September 15, 2007;
110(6):
1739 - 1747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825
Blood,
May 1, 2007;
109(9):
4006 - 4015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Buitenhuis, L. P. Verhagen, J. Cools, and P. J. Coffer
Molecular Mechanisms Underlying FIP1L1-PDGFRA-Mediated Myeloproliferation
Cancer Res.,
April 15, 2007;
67(8):
3759 - 3766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-N. Yeh, T.-W. Chen, H.-L. Lee, Y.-Y. Liu, T.-C. Chao, T.-L. Hwang, Y.-Y. Jan, and M.-F. Chen
Kinase Mutations and Imatinib Mesylate Response for 64 Taiwanese with Advanced GIST: Preliminary Experience from Chang Gung Memorial Hospital
Ann. Surg. Oncol.,
March 1, 2007;
14(3):
1123 - 1128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. G. Roberts, A. F. Odell, E. M. Byrnes, R. M. Baleato, R. Griffith, A. B. Lyons, and L. K. Ashman
Resistance to c-KIT kinase inhibitors conferred by V654A mutation
Mol. Cancer Ther.,
March 1, 2007;
6(3):
1159 - 1166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, F. Giles, A. Quintas-Cardama, and J. Cortes
Important Therapeutic Targets in Chronic Myelogenous Leukemia
Clin. Cancer Res.,
February 15, 2007;
13(4):
1089 - 1097.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Dicker, A. P. Kater, C. E. Prada, T. Fukuda, J. E. Castro, G. Sun, J. Y. Wang, and T. J. Kipps
CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53
Blood,
November 15, 2006;
108(10):
3450 - 3457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Corbacioglu, M. Kilic, M.-A. Westhoff, D. Reinhardt, S. Fulda, and K.-M. Debatin
Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand-independent growth and is responsive to a synergistic effect of imatinib and rapamycin
Blood,
November 15, 2006;
108(10):
3504 - 3513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Delbaldo, E. Chatelut, M. Re, A. Deroussent, S. Seronie-Vivien, A. Jambu, P. Berthaud, A. Le Cesne, J.-Y. Blay, and G. Vassal
Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors.
Clin. Cancer Res.,
October 15, 2006;
12(20):
6073 - 6078.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Akin
Molecular Diagnosis of Mast Cell Disorders: A Paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology
J. Mol. Diagn.,
September 1, 2006;
8(4):
412 - 419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Lin, M. A. Glenn, R. J. Harris, A. D. Duckworth, S. Dennett, J. C. Cawley, M. Zuzel, and J. R. Slupsky
c-Abl Expression in Chronic Lymphocytic Leukemia Cells: Clinical and Therapeutic Implications.
Cancer Res.,
August 1, 2006;
66(15):
7801 - 7809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Pirson, F. Baron, N. Meuris, O. Giet, E. Castermans, R. Greimers, I. Di Stefano, A. Gothot, and Y. Beguin
Despite Inhibition of Hematopoietic Progenitor Cell Growth In Vitro, the Tyrosine Kinase Inhibitor Imatinib Does Not Impair Engraftment of Human CD133+ Cells into NOD/SCID{beta}2mNull Mice
Stem Cells,
July 1, 2006;
24(7):
1814 - 1821.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. L. Goss, K. A. Lee, A. Moritz, J. Nardone, E. J. Spek, J. MacNeill, J. Rush, M. J. Comb, and R. D. Polakiewicz
A common phosphotyrosine signature for the Bcr-Abl kinase
Blood,
June 15, 2006;
107(12):
4888 - 4897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Tokarski, J. A. Newitt, C. Y. J. Chang, J. D. Cheng, M. Wittekind, S. E. Kiefer, K. Kish, F. Y.F. Lee, R. Borzillerri, L. J. Lombardo, et al.
The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants
Cancer Res.,
June 1, 2006;
66(11):
5790 - 5797.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. B. Sambol, G. Ambrosini, R. C. Geha, P. T. Kennealey, P. DeCarolis, R. O'Connor, Y. V. Wu, M. Motwani, J.-H. Chen, G. K. Schwartz, et al.
Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells
Cancer Res.,
June 1, 2006;
66(11):
5858 - 5866.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. W. Parcells, A. K. Ikeda, T. Simms-Waldrip, T. B. Moore, and K. M. Sakamoto
FMS-Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia
Stem Cells,
May 1, 2006;
24(5):
1174 - 1184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Z. Carter, D. H. Mak, W. D. Schober, M. Cabreira-Hansen, M. Beran, T. McQueen, W. Chen, and M. Andreeff
Regulation of survivin expression through Bcr-Abl/MAPK cascade: targeting survivin overcomes imatinib resistance and increases imatinib sensitivity in imatinib-responsive CML cells
Blood,
February 15, 2006;
107(4):
1555 - 1563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Schittenhelm, S. Shiraga, A. Schroeder, A. S. Corbin, D. Griffith, F. Y. Lee, C. Bokemeyer, M. W.N. Deininger, B. J. Druker, and M. C. Heinrich
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
Cancer Res.,
January 1, 2006;
66(1):
473 - 481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Benjamin, C. D. Blanke, J.-Y. Blay, S. Bonvalot, and B. Eisenberg
Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies
Oncologist,
January 1, 2006;
11(1):
9 - 20.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Arora and E. M. Scholar
Role of Tyrosine Kinase Inhibitors in Cancer Therapy
J. Pharmacol. Exp. Ther.,
December 1, 2005;
315(3):
971 - 979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. McLean, M. Gana-Weisz, B. Hartzoulakis, R. Frow, J. Whelan, D. Selwood, and C. Boshoff
Imatinib binding and cKIT inhibition is abrogated by the cKIT kinase domain I missense mutation Val654Ala
Mol. Cancer Ther.,
December 1, 2005;
4(12):
2008 - 2015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Dy, A. A. Miller, S. J. Mandrekar, M.-C. Aubry, R. M. Langdon Jr., R. F. Morton, S. E. Schild, J. R. Jett, and A. A. Adjei
A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study
Ann. Onc.,
November 1, 2005;
16(11):
1811 - 1816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz
Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity
J. Immunol.,
September 15, 2005;
175(6):
3674 - 3680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Appel, S. Balabanov, T. H. Brummendorf, and P. Brossart
Effects of Imatinib on Normal Hematopoiesis and Immune Activation
Stem Cells,
September 1, 2005;
23(8):
1082 - 1088.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Carter, L. M. Wodicka, N. P. Shah, A. M. Velasco, M. A. Fabian, D. K. Treiber, Z. V. Milanov, C. E. Atteridge, W. H. Biggs III, P. T. Edeen, et al.
Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases
PNAS,
August 2, 2005;
102(31):
11011 - 11016.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A Juurikivi, C Sandler, K A Lindstedt, P T Kovanen, T Juutilainen, M J Leskinen, T Maki, and K K Eklund
Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis
Ann Rheum Dis,
August 1, 2005;
64(8):
1126 - 1131.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-M. Tsang, C.-K. Wong, W.-K. Ip, and C. W.-K. Lam
Synergistic effect of SCF and TNF-{alpha} on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells
J. Leukoc. Biol.,
July 1, 2005;
78(1):
239 - 247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
