Abstract
Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal A, Seigel R, Ward E, Murray T, Xu J, Smigal C et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130.
Bene M, Bernier M, Casasnovas R, Castoldi G, Doekharan D, van der Holt B et al. Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients. Br J Haematol 2001; 113: 737–745.
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10: 1911–1918.
Kiyoi H, Ohno R, Ueda R, Saito H, Naoe T . Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 2002; 21: 2555–2563.
Wilhelm S, Carter C, Tang L, Wilkie D, McNabola A, Rong H et al. BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases ivolved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099–7109.
Fabian M, Biggs Wr, Treiber D, Atteridge C, Azimioara M, Benedetti M et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005; 23: 329–336.
Quentmeier H, Reinhardt J, Zaborski M, Drexler H . FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 2003; 17: 120–124.
Zheng R, Levis M, Piloto O, Brown P, Baldwin B, Gorin N et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 2004; 103: 267–274.
Stong R, Korsmeyer S, Parkin J, Arthur D, Kersey J . Human acute leukemia cell line with the t(4;11) chromosomal rearrangement exhibits B lineage and monocytic characteristics. Blood 1985; 65: 21–31.
Griffin J, Leung J, Bruner R, Caligiuri M, Briesewitz R . Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci USA 2003; 100: 7830–7835.
Lierman E, Folens C, Stover E, Mentens N, Van Miegroet H, Scheers W et al. Sorafenib (BAY43-9006) is a potent inhibitor of FIP1L1-PDGFR{alpha} and the imatinib resistant FIP1L1-PDGFR{alpha} T674I mutant. Blood 2006; 108: 1374–1376.
Yao QNR, Kitamura T, Kersey JH . Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway. Leukemia 2005; 19: 1605–1612.
Spiekermann K, Bagrintseva K, Schwab R, Schmieja K, Hiddemann W . Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clin Cancer Res 2003; 9: 2140–2150.
Levis M, Small D . FLT3: ITDoes matter in leukemia. Leukemia 2003; 17: 1738–1752.
Grundler R, Thiede C, Miething C, Steudel C, Peschel C, Duyster J . Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 2003; 102: 646–651.
Ciolli S, Vannucchi A, Leoni F, Nozzoli C, Longo G, Salati A et al. Internal tandem duplications of Flt3 gene (Flt3/ITD) predicts a poor post-remission outcome in adult patients with acute non-promyelocytic leukemia. Leuk Lymphoma 2004; 45: 73–78.
Levis M, Small D . FLT3 tyrosine kinase inhibitors. Int J Hematol 2005; 82: 100–107.
Crump M . Inhibition of raf kinase in the treatment of acute myeloid leukemia. Curr Pharm Des 2002; 8: 2243–2248.
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.
Ricciardi M, McQueen T, Chism D, Milella M, Estey E, Kaldjian E et al. Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia. Leukemia 2005; 19: 1543–1549.
Baines P, Fisher J, Truran L, Davies E, Hallett M, Hoy T et al. The MEK inhibitor, PD98059, reduces survival but does not block acute myeloid leukemia blast maturation in vitro. Eur J Haematol 2000; 64: 211–218.
James J, Smith M, Court E, Yip C, Ching Y, Willson C et al. An investigation of the effects of the MEK inhibitor U0126 on apoptosis in acute leukemia. Hematol J 2003; 4: 427–432.
Lunghi P, Tabilio A, Dall'Aglio P, Ridolo E, Carlo-Stella C, Pelicci P et al. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia 2003; 17: 1783–1793.
Morgan M, Dolp O, Reuter C . Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood 2001; 97: 1823–1834.
Beghini A, Ripamonti C, Cairoli R, Cazzaniga G, Colapietro P, Elice F et al. KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Haematologica 2004; 89: 920–925.
Foss B, Ulvestad E, Bruserud O . Platelet-derived growth factor (PDGF) in human acute myelogenous leukemia: PDGF receptor expression, endogenous PDGF release and responsiveness to exogenous PDGF isoforms by in vitro cultured acute myelogenous leukemia blasts. Eur J Haematol 2001; 67: 267–278.
Verstovsek S, Estey E, Manshouri T, Giles F, Cortes J, Beran M et al. Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol 2002; 118: 151–156.
Rocnik J, Okabe R, Yu J-C, Lee B, Giese N, Schenkein D et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 2006; 108: 1339–1345.
Knapper S, Mills K, Gilkes A, Austin S, Walsh V, Burnett A . The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3 mutated and wild type cases. Blood 2006; 108: 3494–3503.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Auclair, D., Miller, D., Yatsula, V. et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 21, 439–445 (2007). https://doi.org/10.1038/sj.leu.2404508
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404508
Keywords
This article is cited by
-
Small molecules in targeted cancer therapy: advances, challenges, and future perspectives
Signal Transduction and Targeted Therapy (2021)
-
Nucleoside-Lipid-Based Nanocarriers for Sorafenib Delivery
Nanoscale Research Letters (2018)
-
ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition
Leukemia (2017)
-
The Future of Targeting FLT3 Activation in AML
Current Hematologic Malignancy Reports (2017)
-
Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification
Scientific Reports (2015)