Abstract
Raf/MEK/Erk signaling is activated in the majority of acute myeloid leukemias (AMLs), providing rationale for targeting this pathway with therapeutic intent. We investigated growth-inhibitory and proapoptotic effects of sorafenib in AML. Our studies demonstrated that sorafenib significantly inhibited the phosphorylation levels of Raf downstream target proteins MEK1/2 and Erk, induced apoptosis and inhibited colony formation in AML cell lines and in primary AML samples. Mechanistically, treatment with sorafenib resulted in upregulation of proapoptotic Bim, accompanied by an increase in Bad, Bax and Bak protein levels and decreased Mcl-1, X-linked inhibitor of apoptosis and surviving levels, which mainly led to the activation of the intrinsic apoptotic pathway. Silencing of Bim protein expression significantly abrogated sorafenib-induced apoptosis, suggesting a critical function of Bim in the activation of the intrinsic mitochondrial pathway induced by sorafenib. Importantly, sorafenib also modulated phospho-Erk, Bim, Bax and Mcl-1 levels in samples procured from patients in an ongoing Phase I clinical trial of sorafenib in AML. Combination of sorafenib with cytarabine or the novel small molecule Bcl-2 inhibitor ABT-737 synergistically induced cell death in AML cell lines. Our results strongly suggest potential activity of sorafenib as a novel mechanism-based therapeutic agent in AML.
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References
Beeram M, Patnaik A, Rowinsky EK . Regulation of c-Raf-1: therapeutic implications. Clin Adv Hematol Oncol 2003; 1: 476–481.
Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3: 11–22.
Ricciardi MR, 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.
Kornblau SM, Milella M, Ball G, Qiu YH, Ruvolo P, Estrov Z et al. ERK2 and phospho-ERK2 are prognostic for survival in AML and complement the prognostic impact of Bax and BCL-2. Blood 2001; 98: 716a (abstract [2991]).
Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 2006; 108: 2358–2365.
Lenferink AE, Simpson JF, Shawver LK, Coffey RJ, Forbes JT, Arteaga CL . Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu+MMTV/TGF-alpha bigenic mice. Blood 2001; 98: 2991.
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME . Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286: 1358–1362.
Adams JM . Ways of dying: multiple pathways to apoptosis. Genes Dev 2003; 17: 2481–2495.
Yu YL, Chiang YJ, Chen YC, Papetti M, Juo CG, Skoultchi AI et al. MAPK-mediated phosphorylation of GATA-1 promotes Bcl-XL expression and cell survival. J Biol Chem 2005; 280: 29533–29542.
Zheng B, Fiumara P, Li Y, Georgakis GV, Snell V, Younes M et al. MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. Blood 2003; 102: 1019–1027.
Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A . The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3: 287–296.
Marani M, Tenev T, Hancock D, Downward J, Lemoine NR . Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002; 22: 3577–3589.
Lowinger TB, Riedl B, Dumas J, Smith RA . Design and discovery of small molecules targeting raf-1 kinase. Curr Pharm Des 2002; 8: 2269–2278.
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099–7109.
Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 2005; 5: 188–196.
Lee JT, McCubrey JA . BAY-43-9006 Bayer/Onyx. Curr Opin Investig Drugs 2003; 4: 757–763.
Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23: 965–972.
Adnane L, Trail PA, Taylor I, Wilhelm SM . Sorafenib (BAY 43-9006, Nexavar((R))), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2005; 407: 597–612.
Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J . The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica 2007; 92: 27–34.
Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007; 21: 439–445.
Zhang W, Konopleva M, Shi Y, McQween T, Harris D, Small D et al. Sorafenib (BAY 43-9006) directly targets FLT3-ITD in acute myelogenous leukemia. Blood 2006; 108: 149a (abstract [255]).
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677–681.
Clodi K, Kliche K-O, Zhao S, Weidner D, Schenk T, Consoli U et al. Cell-surface exposure of phosphatidylserine correlates with the stage of fludarabine-induced apoptosis in chronic lymphocytic leukemia (CLL) and expression of apoptosis-regulating genes. Cytometry 2000; 40: 19–25.
Zhang W, McQueen T, Schober W, Rassidakis G, Andreeff M, Konopleva M . Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation. Leukemia 2005; 19: 1977–1984.
Estrov Z, Black RA, Sleath PR, Harris D, Van Q, LaPushin R et al. Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation. Blood 1995; 86: 4594–4602.
Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 2001; 108: 851–859.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR et al. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 2005; 17: 525–535.
Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002; 2: 183–192.
Carter BZ, Milella M, Altieri DC, Andreeff M . Cytokine-regulated expression of survivin in myeloid leukemia. Blood 2001; 97: 2784–2790.
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.
Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 2002; 415: 922–926.
Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJ . Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA 2004; 101: 15313–15317.
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375–388.
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270: 1326–1331.
Dent P, Grant S . Pharmacologic interruption of the mitogen-activated extracellular-regulated kinase/mitogen-activated protein kinase signal transduction pathway: potential role in promoting cytotoxic drug action. Clin Cancer Res 2001; 7: 775–783.
Jarvis WD, Fornari Jr FA, Tombes RM, Erukulla RK, Bittman R, Schwartz GK et al. Evidence for involvement of mitogen-activated protein kinase, rather than stress-activated protein kinase, in potentiation of 1-beta-D-arabinofuranosylcytosine-induced apoptosis by interruption of protein kinase C signaling. Mol Pharmacol 1998; 54: 844–856.
Bincoletto C, Saad ST, da Silva ES, Queiroz ML . Haematopoietic response and bcl-2 expression in patients with acute myeloid leukaemia. Eur J Haematol 1999; 62: 38–42.
Acknowledgements
We thank Ms Wenjing Chen for valued assistance in the collection of the patient clinical information and Ms Betty L Notzon for critical review of this paper. This work supported in part by grants from the National Institutes of Health CA55164 and CA100632 (to MA and MK) and a Leukemia SPORE (CA100632) Career Development Award (to WZ).
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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Zhang, W., Konopleva, M., Ruvolo, V. et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 22, 808–818 (2008). https://doi.org/10.1038/sj.leu.2405098
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DOI: https://doi.org/10.1038/sj.leu.2405098
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