Abstract
Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3–5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective.
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
Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM . Philadelphia chromosome-positive acute lymphoblastic leukemia—current concepts and future perspectives. Rev Clin Exp Hematol 2002; 6: 142–160.
Ren R . Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005; 5: 172–183.
Danhauser-Riedl S, Warmuth M, Druker BJ, Emmerich B, Hallek M . Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res 1996; 56: 3589–3596.
Lionberger JM, Wilson MB, Smithgall TE . Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck. J Biol Chem 2000; 275: 18581–18585.
Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 2002; 21: 5766–57674.
Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004; 36: 453–461.
Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.
Dai Y, Rahmani M, Corey SJ, Dent P, Grant S . A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2. J Biol Chem 2004; 279: 34227–34239.
Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 2008; 14: 352–359.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399–401.
O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65: 4500–4505.
Keam SJ . Dasatinib: in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. BioDrugs 2008; 22: 59–69.
Christopher LJ, Cui D, Wu C, Luo R, Manning JA, Bonacorsi SJ et al. Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab Dispos 2008; 36: 1357–1364.
Shah NP, Kasap C, Weier C, Balbas M, Nicoll JM, Bleickardt E et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell 2008; 14: 485–493.
Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and-intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26: 3204–3212.
Mishra S, Zhang B, Cunnick JM, Heisterkamp N, Groffen J . Resistance to imatinib of Bcr/abl p190 lymphoblastic leukemia cells. Cancer Res 2006; 66: 5387–5393.
Kaur P, Feldhahn N, Zhang B, Trageser D, Müschen M, Pertz V et al. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia. Mol Cancer 2007; 6: 67.
Zhang B, Groffen J, Heisterkamp N . Increased resistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblastic leukemia cells. Leukemia 2007; 21: 1189–1197.
Mishra S, Pertz V, Zhang B, Kaur P, Shimada H, Groffen J et al. Treatment of P190 Bcr/Abl lymphoblastic leukemia cells with inhibitors of the serine/threonine kinase CK2. Leukemia 2007; 21: 178–180.
Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 11: 2190–2196.
Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004; 47: 6658–6661.
Nam S, Williams A, Vultur A, List A, Bhalla K, Smith D et al. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol Cancer Ther 2007; 6: 1400–1405.
Jin L, Tabe Y, Konoplev S, Xu Y, Leysath CE, Lu H et al. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol Cancer Ther 2008; 7: 48–58.
Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 1997; 139: 651–664.
Schols D, Struyf S, Van Damme J, Esté JA, Henson G, De Clercq E . Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 1997; 186: 1383–1388.
Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y et al. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res 2008; 32: 980–983.
Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 2009; 27: 469–471.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531–2541.
Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007; 110: 2309–2315.
Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S . Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA 2006; 103: 16870–16875.
Okabe S, Tauchi T, Ohyashiki K . Characteristics of dasatinib- and imatinib-resistant chronic myelogenous leukemia cells. Clin Cancer Res 2008; 14: 6181–6186.
Weisberg E, Wright RD, McMillin DW, Mitsiades C, Ray A, Barrett R et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. Mol Cancer Ther 2008; 7: 1121–1129.
Glodek AM, Honczarenko M, Le Y, Campbell JJ, Silberstein LE . Sustained activation of cell adhesion is a differentially regulated process in B lymphopoiesis. J Exp Med 2003; 197: 461–473.
Dillmann F, Veldwijk MR, Laufs S, Sperandio M, Calandra G, Wenz F et al. Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to imatinib and nilotinib. Leuk Lymph 2009; 50: 1676–1686.
Tarasova NI, Stauber RH, Michejda CJ . Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4. J Biol Chem 1998; 273: 15883–15886.
Patrussi L, Baldari CT . Intracellular mediators of CXCR4-dependent signaling in T cells. Immunol Lett 2008; 115: 75–82.
Wong D, Kortz W . Translating an antagonist of chemokine receptor CXCR4 from bench to bedside. Clin Can Res 2008; 14: 7975–7980.
Acknowledgements
We thank Reshmi Parameswaran for helpful suggestions and critical reading of the paper. This work was supported by PHS Grants CA090321 (to NH) and R01CA137060 and RO1CA139032 (MM), by funding from a CHLA RCDA, a Jean Perkins Scholar and a StopCancer award (Y-mK); and by a private donor (Y-mK, MM, NH, JG).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Fei, F., Stoddart, S., Müschen, M. et al. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 24, 813–820 (2010). https://doi.org/10.1038/leu.2009.302
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2009.302
Keywords
This article is cited by
-
Leukaemia: a model metastatic disease
Nature Reviews Cancer (2021)
-
Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008
Journal of Experimental & Clinical Cancer Research (2018)
-
Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program
BMC Cancer (2016)
-
STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention
Leukemia (2014)
-
A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo
Scientific Reports (2014)