BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients

  • Mark R. Litzow
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)

Summary

The discovery of a translocation between the Abelson oncogene (ABL1) on the long arm of chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22 resulting in the BCR-ABL1 gene mutation was a landmark discovery in the pathogenesis of human leukemia. The decades of research into the structure and function of this aberrant gene culminated in development of imatinib mesylate, which has had an astounding benefit in the treatment of this disease. Despite its resounding success, a minority of patients developed resistance to imatinib. The unraveling of the multiple resistance mechanisms and the discovery of the dominant mechanism of point mutations in the ABL1 kinase portion of BCR-ABL1 has led to the development of second and subsequent generation agents that are active against these mutations. Dasatinib (Sprycel®) has rapidly achieved FDA approval for imatinib-resistant and intolerant CML. Nilotinib (Tasigna®) is undergoing FDA review. A host of other kinase inhibitors are in earlier stages of pre-clinical and clinical development. The structure–function relationships of imatinib in complex with BCR-ABL1 and the development of these new agents will certainly result in the use of combination therapy for CML and likely result in excellent long-term disease control and a probable cure. These developments have fueled the development of targeted therapy in multiple other malignancies and diseases and represent the beginnings of a golden age in the treatment of human disease.

Key Words

Chronic myeloid leukemia imatinib resistance BCR-ABL1 Mutations dasatinib nilotinib tyrosine kinase inhibitors 

Notes

Acknowledgment

The author gratefully acknowledges Mrs. Denise Chase for transcription and development of this manuscript.

References

  1. 1.
    Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.Google Scholar
  2. 2.
    Druker BJ, Tamura S, Buchdunger E et al. Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 1996;2:561–566.PubMedCrossRefGoogle Scholar
  3. 3.
    Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–293.PubMedCrossRefGoogle Scholar
  4. 4.
    Shtivelman E, Lifshitz B, Gale RP et al. Fused transcript of ABL and BCR genes in chronic myelogenous leukaemia. Nature 1985;315:550–554.PubMedCrossRefGoogle Scholar
  5. 5.
    Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210BCR/ABL gene of the Philadelphia chromosome. Science 1990;247:824–830.PubMedCrossRefGoogle Scholar
  6. 6.
    Faderl S, Talpaz M, Estrov Z et al. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164–172.PubMedCrossRefGoogle Scholar
  7. 7.
    Eaves CJ, Eaves AC. Progenitor cell dynamics. In: Carella AM, Daley GQ, Eaves CJ eds. Chronic myeloid leukaemia: biology and treatment. London: Martin Dunitz; 2001:73–100.Google Scholar
  8. 8.
    Gordon MY, Dowding CR, Riley GP et al. Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature 1987;328:342–344.PubMedCrossRefGoogle Scholar
  9. 9.
    Verfaillie CM, Hurley R, Zhao RC et al. Pathophysiology of CML: do defects in integrin function contribute to the premature circulation and massive expansion of the BCR/ABL positive clone? J Lab Clin Med 1997;129:584–591.PubMedCrossRefGoogle Scholar
  10. 10.
    Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med 2001;7:228–234.PubMedCrossRefGoogle Scholar
  11. 11.
    Goldman JM, Melo JV. Chronic myeloid leukemia: advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451–1464.PubMedCrossRefGoogle Scholar
  12. 12.
    Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003;112:831–843.PubMedCrossRefGoogle Scholar
  13. 13.
    Azam M, Daley GQ. Anticipating clinical resistance to target-directed agents: the BCR-ABL paradigm. Mol Diagn Ther 2006;10:67–76.PubMedGoogle Scholar
  14. 14.
    Thomas ED, Clift RA, Fefer A et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986;104:155–163.PubMedGoogle Scholar
  15. 15.
    Guilhot F, Roy L, Guilhot J et al. Interferon therapy in chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004;18:585-603, viii.PubMedCrossRefGoogle Scholar
  16. 16.
    Guilhot F. Sustained durability of responses plus high rates of cytogenetic responses result in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) treated with imatinib (IM) therapy: update from the IRIS study. (abst #21). Blood 2004;104:10a.Google Scholar
  17. 17.
    Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. J Natl Cancer Inst 1997;89:1616–1620.Google Scholar
  18. 18.
    Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037.PubMedCrossRefGoogle Scholar
  19. 19.
    Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–1042.PubMedCrossRefGoogle Scholar
  20. 20.
    Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–652.PubMedCrossRefGoogle Scholar
  21. 21.
    Talpaz M, Silver RT, Druker BJ et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:1928–1937.PubMedCrossRefGoogle Scholar
  22. 22.
    Sawyers CL, Hochhaus A, Feldman E et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530–3539.PubMedCrossRefGoogle Scholar
  23. 23.
    Ottmann OG, Druker BJ, Sawyers CL et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002;100:1965–1971.PubMedCrossRefGoogle Scholar
  24. 24.
    O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004.PubMedCrossRefGoogle Scholar
  25. 25.
    Hughes TP, Kaeda J, Branford S et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423–1432.PubMedCrossRefGoogle Scholar
  26. 26.
    Druker BJ, Guilhot F, O'Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408–2417.PubMedCrossRefGoogle Scholar
  27. 27.
    Mauro MJ. Defining and managing imatinib resistance. Hematology Am Soc Hematol Educ Program 2006:219–225.Google Scholar
  28. 28.
    Hughes T, Deininger M, Hochhaus A et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28–37.PubMedCrossRefGoogle Scholar
  29. 29.
    Branford S, Cross NC, Hochhaus A et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006;20:1925–1930.PubMedCrossRefGoogle Scholar
  30. 30.
    Ross DM, Branford S, Moore S et al. Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL. Leukemia 2006;20:664–670.PubMedCrossRefGoogle Scholar
  31. 31.
    Baccarani M, Saglio G, Goldman J et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood 2006;108:1809–1820.PubMedCrossRefGoogle Scholar
  32. 32.
    Mahon FX, Deininger MW, Schultheis B et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000;96:1070–1079.PubMedGoogle Scholar
  33. 33.
    Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876–880.PubMedCrossRefGoogle Scholar
  34. 34.
    Hochhaus A, Kreil S, Corbin AS et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16:2190–2196.PubMedCrossRefGoogle Scholar
  35. 35.
    Gambacorti-Passerini C, Barni R, le Coutre P et al. Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the ABL inhibitor STI571. J Natl Cancer Inst 2000;92:1641–1650.PubMedCrossRefGoogle Scholar
  36. 36.
    Larghero J, Leguay T, Mourah S et al. Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo. Biochem Pharmacol 2003;66:1907–1913.PubMedCrossRefGoogle Scholar
  37. 37.
    le Coutre P, Kreuzer KA, Na IK et al. Determination of alpha-1 acid glycoprotein in patients with Ph+ chronic myeloid leukemia during the first 13 weeks of therapy with STI571. Blood Cells Mol Dis 2002;28:75–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Thomas J, Wang L, Clark RE et al. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:3739–3745.PubMedCrossRefGoogle Scholar
  39. 39.
    White DL, Saunders VA, Dang P et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006;108:697–704.PubMedCrossRefGoogle Scholar
  40. 40.
    Shimizu T, Miyakawa Y, Iwata S et al. A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1: role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein. Exp Hematol 2004;32:1057–1063.PubMedCrossRefGoogle Scholar
  41. 41.
    Larson RA, Druker B, Guilhot F et al. Correlation of pharmacokinetic data with cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib-An analysis of IRIS study data (Abstract 429). Blood 2006;108:131a.CrossRefGoogle Scholar
  42. 42.
    Illmer T, Schaich M, Platzbecker U et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004;18:401–408.PubMedCrossRefGoogle Scholar
  43. 43.
    Wendel HG, de Stanchina E, Cepero E et al. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proc Natl Acad Sci USA 2006;103:7444–7449.PubMedCrossRefGoogle Scholar
  44. 44.
    Donato NJ, Wu JY, Stapley J et al. BCR-ABL independence and LYN kinase over-expression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003;101:690–698.PubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    Warmuth M, Simon N, Mitina O et al. Dual-specific SRC and ABL kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant BCR-ABL kinases. Blood 2003;101:664–672.PubMedCrossRefGoogle Scholar
  47. 47.
    Wilson MB, Schreiner SJ, Choi HJ et al. Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for SRC family kinases in BCR-ABL signal transduction and oncogenesis. Oncogene 2002;21:8075–8088.PubMedCrossRefGoogle Scholar
  48. 48.
    Ptasznik A, Nakata Y, Kalota A et al. Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med 2004;10:1187–1189.PubMedCrossRefGoogle Scholar
  49. 49.
    Donato N, Wu J, Kong LY et al. Constitutive activation of SRC-family kinases in chronic myelogenous leukemia patients resistant to imatinib mesylate in the absence of BCR-ABL mutations: a rationale use of SRC/ABL dual kinase inhibitor-based therapy (Abstract 1087). Blood 2005;106:316a.Google Scholar
  50. 50.
    Hantschel O, Nagar B, Guettler S et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 2003;112:845–857.PubMedCrossRefGoogle Scholar
  51. 51.
    Nagar B, Hantschel O, Young MA et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 2003;112:859–871.PubMedCrossRefGoogle Scholar
  52. 52.
    Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett2007;249:121–132. Review.PubMedCrossRefGoogle Scholar
  53. 53.
    Nardi V, Azam M, Daley GQ. Mechanisms and implications of imatinib resistance mutations in BCR-ABL. Curr Opin Hematol 2004;11:35–43.PubMedCrossRefGoogle Scholar
  54. 54.
    Pluk H, Dorey K, Superti-Furga G. Autoinhibition of c-Abl. Cell 2002;108:247–259.PubMedCrossRefGoogle Scholar
  55. 55.
    Schindler T, Bornmann W, Pellicena P et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938–1942.PubMedCrossRefGoogle Scholar
  56. 56.
    Yamamoto M, Kurosu T, Kakihana K et al. The two major imatinib resistance mutations, E255 K and T315I, enhance the activity of BCR/ABL fusion kinase. Biochem Biophys Res Commun 2004;319:1272–1275.PubMedCrossRefGoogle Scholar
  57. 57.
    Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N et al. Several types of mutations of the ABL gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002;100:1014–1018.PubMedCrossRefGoogle Scholar
  58. 58.
    Hofmann WK, Komor M, Wassmann B et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 2003;102: 659–661.PubMedCrossRefGoogle Scholar
  59. 59.
    Shah NP, Nicoll JM, Nagar B et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117–125.PubMedCrossRefGoogle Scholar
  60. 60.
    Willis SG, Lange T, Demehri S et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005;106:2128–2137.PubMedCrossRefGoogle Scholar
  61. 61.
    Griswold IJ, MacPartlin M, Bumm T et al. Kinase domain mutants of BCR-ABL exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Mol Cell Biol 2006;26:6082–6093.PubMedCrossRefGoogle Scholar
  62. 62.
    Deininger M. Resistance to imatinib: mechanisms and management. J Natl Compr Canc Netw 2005;3:757–768.PubMedGoogle Scholar
  63. 63.
    Corbin AS, La Rosee P, Stoffregen EP et al. Several BCR-ABL kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 2003;101:4611–4614.PubMedCrossRefGoogle Scholar
  64. 64.
    Branford S, Rudzki Z, Walsh S et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102:276–283.PubMedCrossRefGoogle Scholar
  65. 65.
    Soverini S, Martinelli G, Rosti G et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005;23:4100–4109.PubMedCrossRefGoogle Scholar
  66. 66.
    Nicolini FE, Corm S, Le QH et al. Mutation status and clinical outcome of 89 imatinib mesylate–resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 2006;20:1061–1066.PubMedCrossRefGoogle Scholar
  67. 67.
    Jabbour E, Kantarjian H, Jones D et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006;20: 1767–1773.PubMedCrossRefGoogle Scholar
  68. 68.
    Hofmann WK, de Vos S, Elashoff D et al. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 2002;359:481–486.PubMedCrossRefGoogle Scholar
  69. 69.
    McLean LA, Gathmann I, Capdeville R et al. Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib. Clin Cancer Res 2004;10:155–165.PubMedCrossRefGoogle Scholar
  70. 70.
    Villuendas R, Steegmann JL, Pollan M et al. Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach. Leukemia 2006;20:1047–1054.PubMedCrossRefGoogle Scholar
  71. 71.
    Chung YJ, Kim TM, Kim DW et al. Gene expression signatures associated with the resistance to imatinib. Leukemia 2006;20:1542–1550.PubMedCrossRefGoogle Scholar
  72. 72.
    Frank O, Brors B, Fabarius A et al. Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients. Leukemia 2006;20:1400–1407.PubMedCrossRefGoogle Scholar
  73. 73.
    Soverini S, Martinelli G, Amabile M et al. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib. Clin Chem 2004;50:1205–1213.PubMedCrossRefGoogle Scholar
  74. 74.
    Jacobberger JW, Sramkoski RM, Frisa PS et al. Immunoreactivity of Stat5 phosphorylated on tyrosine as a cell-based measure of BCR-ABL kinase activity. Cytometry A 2003;54:75–88.PubMedCrossRefGoogle Scholar
  75. 75.
    Liu WH, Makrigiorgos GM. Sensitive and quantitative detection of mutations associated with clinical resistance to STI-571. Leuk Res 2003;27:979–982.PubMedCrossRefGoogle Scholar
  76. 76.
    Kreuzer KA, Le Coutre P, Landt O et al. Pre-existence and evolution of imatinib mesylate–resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique. Ann Hematol 2003;82:284–289.PubMedCrossRefGoogle Scholar
  77. 77.
    Cazzaniga G, Corradi B, Piazza R et al. Highly sensitive mutations detection in BCR-ABL positive leukemia prior and during imatinib treatment (Abstract 1985). Blood 2004;104:548a.Google Scholar
  78. 78.
    Branford S, Rudzki Z, Parkinson I et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004;104:2926–2932.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang L, Knight K, Lucas C et al. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006;91:235–239.PubMedGoogle Scholar
  80. 80.
    Kantarjian HM, Talpaz M, O'Brien S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101: 473–475.PubMedCrossRefGoogle Scholar
  81. 81.
    Kantarjian HM, Cortes JE, O'Brien S et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 2004;104: 1979–1988.PubMedCrossRefGoogle Scholar
  82. 82.
    Gambacorti-Passerini CB, Rossi F, Verga M et al. Differences between in vivo and in vitro sensitivity to imatinib of Bcr/Abl+ cells obtained from leukemic patients. Blood Cells Mol Dis 2002;28:361–372.PubMedCrossRefGoogle Scholar
  83. 83.
    Liu NS, O'Brien S. Spontaneous reversion from blast to chronic phase after withdrawal of imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma 2002;43:2413–2415.PubMedCrossRefGoogle Scholar
  84. 84.
    Muller MC, Lahaye T, Hochhaus A. [Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells]. Dtsch Med Wochenschr 2002;127:2205–2207.PubMedCrossRefGoogle Scholar
  85. 85.
    Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 2004;18:1321–1331.PubMedCrossRefGoogle Scholar
  86. 86.
    Dorsey JF, Jove R, Kraker AJ et al. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res 2000;60:3127–3131.PubMedGoogle Scholar
  87. 87.
    La Rosee P, Corbin AS, Stoffregen EP et al. Activity of the BCR-ABL kinase inhibitor PD180970 against clinically relevant BCR-ABL isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 2002;62:7149–7153.PubMedGoogle Scholar
  88. 88.
    Huron DR, Gorre ME, Kraker AJ et al. A novel pyridopyrimidine inhibitor of ABL kinase is a picomolar inhibitor of BCR-ABL-driven K562 cells and is effective against STI571-resistant BCR-ABL mutants. Clin Cancer Res 2003;9:1267–1273.PubMedGoogle Scholar
  89. 89.
    O'Hare T, Pollock R, Stoffregen EP et al. Inhibition of wild-type and mutant BCR-ABL by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 2004;104: 2532–2539.PubMedCrossRefGoogle Scholar
  90. 90.
    Deininger MW, Druker BJ. SRCircumventing imatinib resistance. Cancer Cell2004;6:108–110.PubMedCrossRefGoogle Scholar
  91. 91.
    Shah NP, Tran C, Lee FY et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.PubMedCrossRefGoogle Scholar
  92. 92.
    Tokarski JS, Newitt JA, Chang CY 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 2006;66:5790–5797.PubMedCrossRefGoogle Scholar
  93. 93.
    Talpaz M, Shah NP, Kantarjian H et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 2006;354:2531–2541.PubMedCrossRefGoogle Scholar
  94. 94.
    Hochhaus A, Kantarjian HM, Baccarani M et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007;109:2303–2309.PubMedCrossRefGoogle Scholar
  95. 95.
    Cortes J, Guilhot F, Rosti Get al. Dasatinib (SPRYCEL) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (IM-R) or intolerant (IM-I): updated results of the CA180-005 “START-A” phase II study (Abstract 2160). Blood 2006;108:613a.Google Scholar
  96. 96.
    Cortes J, Rousselot P, Kim DW et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007;109:3207–3213.PubMedCrossRefGoogle Scholar
  97. 97.
    Shah N, Pasquini R, Rousselot P et al. Dasatinib (SPRYCEL) vs. escalated dose of imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib: results of the CA180-017 START-R randomized study (Abstract 167). Blood 2006;108:53a.Google Scholar
  98. 98.
    Quintas-Cardama A, Kantarjian H, Jones Det al. Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood 2007;109:497–499.PubMedCrossRefGoogle Scholar
  99. 99.
    Weisberg E, Manley PW, Breitenstein W et al. Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell 2005;7:129–141.PubMedCrossRefGoogle Scholar
  100. 100.
    O’Hare T, Walters DK, Stoffregen EP 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.PubMedCrossRefGoogle Scholar
  101. 101.
    Kantarjian H, Giles F, Wunderle L et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome–positive ALL. N Engl J Med 2006;354:2542–2551.PubMedCrossRefGoogle Scholar
  102. 102.
    le Coutre P, Bhalla K, Giles F et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib-resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP) (Abstract 165). Blood 2006;108:53a.Google Scholar
  103. 103.
    Kantarjian H, Gattermann N, Hochhaus A et al. A phase II study of nilotinib: a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP) (Abstract 2169). Blood 2006;108:615a.CrossRefGoogle Scholar
  104. 104.
    Giles F, le Coutre P, Bhalla K et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP), or blast crisis (BC) who have also failed dasatinib therapy (Abstract 2170). Blood 2006;108:615a.CrossRefGoogle Scholar
  105. 105.
    Druker BJ. Circumventing resistance to kinase-inhibitor therapy. N Engl J Med 2006;354:2594–2596.PubMedCrossRefGoogle Scholar
  106. 106.
    Bradeen HA, Eide CA, O’Hare T et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 2006;108:2332–2338.PubMedCrossRefGoogle Scholar
  107. 107.
    Burgess MR, Skaggs BJ, Shah NP et al. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA 2005;102:3395–3400.PubMedCrossRefGoogle Scholar
  108. 108.
    Weisberg EL, Catley L, Wright RD et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR/ABL+ leukemias. Blood 2007;109:2112–2120.PubMedCrossRefGoogle Scholar
  109. 109.
    O'Hare T, Walters DK, Stoffregen EP et al. Combined ABL inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: SRC/ABL inhibitors are compatible with imatinib. Clin Cancer Res 2005;11:6987–6993.PubMedCrossRefGoogle Scholar
  110. 110.
    Copland M, Hamilton A, Elrick LJ et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006;107:4532–4539.PubMedCrossRefGoogle Scholar
  111. 111.
    Gumireddy K, Baker SJ, Cosenza SC et al. A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc Natl Acad Sci USA 2005;102:1992–1997.PubMedCrossRefGoogle Scholar
  112. 112.
    Orsolic N, Golemovic M, Quintas-Cardama A et al. Adaphostin has significant and selective activity against chronic and acute myeloid leukemia cells. Cancer Sci 2006;97:952–960.PubMedCrossRefGoogle Scholar
  113. 113.
    Yokota A, Kimura S, Masuda S et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood 2007;109:306-314.PubMedCrossRefGoogle Scholar
  114. 114.
    Kimura S, Niwa T, Hirabayashi K et al. Development of NS-187, a potent and selective dual BCR-ABL/LYN tyrosine kinase inhibitor. Cancer Chemother Pharmacol 2006;58 Suppl 7:55–61.CrossRefGoogle Scholar
  115. 115.
    Golas JM, Arndt K, Etienne C et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of SRC and ABL kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res 2003;63:375–381.PubMedGoogle Scholar
  116. 116.
    Young MA, Shah NP, Chao LH et al. Structure of the kinase domain of an imatinib-resistant ABL mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 2006;66:1007–1014.PubMedCrossRefGoogle Scholar
  117. 117.
    Giles FJ, Cortes J, Jones D et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007;109:500–502.PubMedCrossRefGoogle Scholar
  118. 118.
    Tauchi T, Akahane D, Nunoda K et al. Activity of a novel aurora kinase inhibitor, VE-465, against T315i mutant form of BCR-ABL: in vitro and in vivo studies (Abstract 1358). Blood 2006;108:396a.Google Scholar
  119. 119.
    Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Crit Rev Oncol Hematol 2006;57:145–164.PubMedCrossRefGoogle Scholar
  120. 120.
    Cowan-Jacob SW, Fendrich G, Floersheimer A et al. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr D Biol Crystallogr 2007;63(Pt 1):80–93.PubMedGoogle Scholar
  121. 121.
    Van Etten RA. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res 2004;28 Suppl 1:S21–28.PubMedGoogle Scholar
  122. 122.
    Deininger MW. Basic science going clinical: molecularly targeted therapy of chronic myelogenous leukemia. J Cancer Res Clin Oncol 2004;130:59–72.PubMedCrossRefGoogle Scholar
  123. 123.
    Kantarjian HM, Talpaz M, Giles F et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 2006;145:913–923.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mark R. Litzow
    • 1
  1. 1.Division of Hematology ResearchMayo ClinicRochesterUSA

Personalised recommendations