Current Hematologic Malignancy Reports

, Volume 14, Issue 5, pp 395–404 | Cite as

Molecular Mechanisms of Resistance to Tyrosine Kinase Inhibitors

  • Marjan YaghmaieEmail author
  • Cecilia CS Yeung
Molecular Testing and Diagnostics (J Khoury, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Molecular Testing and Diagnostics


Purpose of Review

Chronic myeloid leukemia (CML) patients with constitutive activity of BCR-ABL1 oncoprotein frequently derive significant clinical benefits from tyrosine kinase inhibitors (TKIs). Point mutations in the ABL1 kinase domain (KD) are an important mechanism of TKI resistance in CML. In this review, we present molecular mechanisms of TKI resistance paying particular attention to drug resistance which allows for a survival advantage in CML.

Recent Findings

Sensitive disease monitoring is a required standard of care for management of CML. Screening of these mutations fail to explain 20–40% of resistant cases where activation of different survival pathways must be the main reason for resistance.


Eliminating TKI resistance appears to be the most successful therapeutic way to decrease leukemic disease burden and potentiate cure. Advances on novel strategies for identifying and confronting drug resistance are rapidly altering management of CML that are resistant to TKI and expanding the landscape of available therapies.


Chronic myeloid leukemia Molecular mechanism Tyrosine kinase inhibitor Resistance mutations 


Compliance with Ethical Standards

Conflict of Interest

Dr. Yeung reports grants from OBI Pharmaceuticals and Pfizer outside the submitted work. Dr. Yaghmaie declares no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300(5894):765–7.PubMedGoogle Scholar
  2. 2.
    Ma L, Shan Y, Bai R, Xue L, Eide CA, Ou J, et al. A therapeutically targetable mechanism of BCR-ABL–independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014;6(252):252ra121.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Soverini S, Mancini M, Bavaro L, Cavo M, Martinelli G. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer. 2018;17(1):49.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Radich J. Structure, function, and resistance in chronic myeloid leukemia. Cancer Cell. 2014;26(3):305–6.PubMedGoogle Scholar
  5. 5.
    Efficace F, Baccarani M, Breccia M, Alimena G, Rosti G, Cottone F, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood. 2011;118(17):4554–60.PubMedGoogle Scholar
  6. 6.
    Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boque C, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123(4):494–500.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898–905.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.PubMedGoogle Scholar
  10. 10.
    Kantarjian HM, Cortes J, O’Brien S, Giles FJ, Albitar M, Rios MB, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase. Blood. 2002;99(10):3547–53.PubMedGoogle Scholar
  11. 11.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.PubMedGoogle Scholar
  12. 12.
    Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010;116(16):3852–61.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study: Presented in part at the 43rd Annual Meeting of The American Society of Hematology, Orlando, FL, December 11, 2001. Blood. 2002;99(10):3530–9.PubMedGoogle Scholar
  14. 14.
    Hughes T, Branford S. Molecular monitoring of BCR–ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev. 2006;20(1):29–41.PubMedGoogle Scholar
  15. 15.
    Branford S, Rudzki Z, Parkinson I, Grigg A, Taylor K, Seymour JF, 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(9):2926–32.PubMedGoogle Scholar
  16. 16.
    Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733–6.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Trivedi D, Landsman-Blumberg P, Darkow T, Smith D, McMorrow D, Mullins CD. Adherence and persistence among chronic myeloid leukemia patients during second-line tyrosine kinase inhibitor treatment. J Manag Care Pharm. 2014;20(10):1006–15.Google Scholar
  18. 18.
    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.PubMedGoogle Scholar
  19. 19.
    Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, 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(15):1423–32.PubMedGoogle Scholar
  20. 20.
    • Steegmann J, Baccarani M, Breccia M, Casado L, García-Gutiérrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30(8):1648. This is the clinical practive guidelines for CML issued by ELN.PubMedPubMedCentralGoogle Scholar
  21. 21.
    •• Patel AB, O’Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol /Oncol Clinics. 2017;31(4):589–612. This study used NGS for detection of ABL1 KD mutations but also detected compound mutations and recognized specific resistance profiles. Google Scholar
  22. 22.
    Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53.PubMedGoogle Scholar
  23. 23.
    Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor–resistant CML: frequency and clonal relationships. Blood. 2013;121(3):489–98.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Eiring AM, Page BD, Kraft IL, Mason CC, Vellore NA, Resetca D, et al. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia. 2015;29(3):586–97.PubMedGoogle Scholar
  25. 25.
    Lamontanara AJ, Gencer EB, Kuzyk O, Hantschel O. Mechanisms of resistance to BCR-ABL and other kinase inhibitors. Biochim Biophys Acta Proteins Proteom. 2013;1834(7):1449–59.Google Scholar
  26. 26.
    Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20(10):1767–73.PubMedGoogle Scholar
  27. 27.
    Lahaye T, Riehm B, Berger U, Paschka P, Müller MC, Kreil S, et al. Response and resistance in 300 patients with BCR-ABL–positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer. 2005;103(8):1659–69.PubMedGoogle Scholar
  28. 28.
    Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15.PubMedGoogle Scholar
  29. 29.
    Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, 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(2):117–25.PubMedGoogle Scholar
  30. 30.
    An X, Tiwari AK, Sun Y, Ding P-R, Ashby CR Jr, Chen Z-S. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34(10):1255–68.PubMedGoogle Scholar
  31. 31.
    Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Yeung CCS, Egan D, Radich JP. Molecular monitoring of chronic myeloid leukemia: present and future. Expert. Rev. Mol. Diagn. 2016;16(10):1083–91.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041–51.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20.PubMedGoogle Scholar
  35. 35.
    Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R et al. Chronic myeloid leukemia, version 1.2019, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network. 2018;16(9):1108–35.PubMedGoogle Scholar
  36. 36.
    Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818–24.PubMedGoogle Scholar
  37. 37.
    Kantarjian HM, Giles F, Quintás-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13(4):1089–97.PubMedGoogle Scholar
  38. 38.
    Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.PubMedGoogle Scholar
  39. 39.
    Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29(11):1046–51.PubMedGoogle Scholar
  40. 40.
    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80.PubMedGoogle Scholar
  41. 41.
    • Talati C, Pinilla-Ibarz J. Resistance in chronic myeloid leukemia: definitions and novel therapeutic agents. Curr Opin Hematol. 2018;25(2):154–61. This reviews definitions of resistance.PubMedGoogle Scholar
  42. 42.
    Hughes TP, Saglio G, Quintas-Cardama A, Mauro MJ, Kim DW, Lipton JH, et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia. 2015;29(9):1832–8.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hochhaus A, Ernst T, Eigendorff E, La Rosee P. Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients. Ann Hematol. 2015;94(Suppl 2):S133–40.PubMedGoogle Scholar
  44. 44.
    Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013;121(16):3165–71.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Shah NP, Sawyers CL. Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene. 2003;22(47):7389–95.PubMedGoogle Scholar
  46. 46.
    Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, 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(1):276–83.PubMedGoogle Scholar
  47. 47.
    Eide CA, O’Hare T. Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors. Curr Hematol Malig Rep. 2015;10(2):158–66.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121(3):489–98.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–41.PubMedGoogle Scholar
  52. 52.
    Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin J. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94(12):1765–9.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Brasher BB, Van Etten RA. c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. J Biol Chem. 2000;275(45):35631–7.PubMedGoogle Scholar
  54. 54.
    Dorey K, Engen JR, Kretzschmar J, Wilm M, Neubauer G, Schindler T, et al. Phosphorylation and structure-based functional studies reveal a positive and a negative role for the activation loop of the c-Abl tyrosine kinase. Oncogene. 2001;20(56):8075–84.PubMedGoogle Scholar
  55. 55.
    Vajpai N, Strauss A, Fendrich G, Cowan-Jacob SW, Manley PW, Grzesiek S, et al. Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem. 2008;283(26):18292–302.PubMedGoogle Scholar
  56. 56.
    Skaggs BJ, Gorre ME, Ryvkin A, Burgess MR, Xie Y, Han Y, et al. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCR-ABL mutants. Proc Natl Acad Sci. 2006;103(51):19466–71.PubMedGoogle Scholar
  57. 57.
    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(3):469–71.PubMedGoogle Scholar
  58. 58.
    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–12.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med. 2012;367(22):2075–88.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Danisz K, Blasiak J. Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors. Acta Biochim Pol. 2013;60(4).Google Scholar
  61. 61.
    O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110(7):2242–9.PubMedGoogle Scholar
  62. 62.
    Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–9.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Larson R, Hochhaus A, Hughes T, Clark R, Etienne G, Kim D, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197–203.PubMedGoogle Scholar
  64. 64.
    Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841–51.PubMedGoogle Scholar
  65. 65.
    •• Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. Chronic Myeloid Leukemia, Version 1.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2018;16(9):1108–35. This is the clinical practice guidelines for CML issued by NCCN. Google Scholar
  66. 66.
    Yeung CC, Egan D, Radich J. New methodologies in the molecular monitoring of CML. Curr Hematol Malig Rep. 2016;11(2):94–101.PubMedGoogle Scholar
  67. 67.
    Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–9.PubMedGoogle Scholar
  68. 68.
    Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M, et al. Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl_7):vii72–vii7.PubMedGoogle Scholar
  69. 69.
    Machova Polakova K, Kulvait V, Benesova A, Linhartova J, Klamova H, Jaruskova M, et al. Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase. J Cancer Res Clin Oncol. 2015;141(5):887–99.PubMedGoogle Scholar
  70. 70.
    •• Soverini S, De Benedittis C, Polakova KM, Linhartova J, Castagnetti F, Gugliotta G, et al. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. Oncotarget. 2016;7(16):21982–90. This study used NGS for detection of ABL1 KD mutations and demonstrated improved sensitivity.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Von Bubnoff N, Peschel C, Duyster J. Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia. 2003;17(5):829–38.Google Scholar
  72. 72.
    Hochhaus A, Kreil S, Corbin A, La Rosee P, Müller M, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16(11):2190–6.PubMedGoogle Scholar
  73. 73.
    Soverini S, De Benedittis C, Polakova KM, Brouckova A, Horner D, Iacono M, et al. Unraveling the complexity of tyrosine kinase inhibitor–resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood. 2013;122(9):1634–48.PubMedGoogle Scholar
  74. 74.
    Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005;65(19):8912–9.PubMedGoogle Scholar
  75. 75.
    Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard M-A, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496–9.PubMedGoogle Scholar
  76. 76.
    Skorski T. Oncogenic tyrosine kinases and the DNA-damage response. Nat Rev Cancer. 2002;2(5):351–60.PubMedGoogle Scholar
  77. 77.
    Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254–64.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Kim TD, Türkmen S, Schwarz M, Koca G, Nogai H, Bommer C, et al. Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia. Haematologica. 2010;95(4):582–8.PubMedGoogle Scholar
  79. 79.
    Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119(6):1501–10.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Yang K, Fu L-w. Mechanisms of resistance to BCR–ABL TKIs and the therapeutic strategies: a review. Crit Rev Oncol Hematol. 2015;93(3):277–92.PubMedGoogle Scholar
  81. 81.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53(1):615–27.PubMedGoogle Scholar
  82. 82.
    Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879–94.PubMedGoogle Scholar
  83. 83.
    White DL, Dang P, Engler J, Frede A, Zrim S, Osborn M, et al. Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol. 2010;28(16):2761–7.PubMedGoogle Scholar
  84. 84.
    White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110(12):4064–72.PubMedGoogle Scholar
  85. 85.
    Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res. 2009;15(24):7519–27.PubMedGoogle Scholar
  86. 86.
    Lu L, Saunders V, Leclercq T, Hughes T, White D. Ponatinib is not transported by ABCB1, ABCG2 or OCT-1 in CML cells. Leukemia. 2015;29(8):1792–4.PubMedGoogle Scholar
  87. 87.
    Eadie L, Hughes T, White D. Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib. Clin Pharmacol Ther. 2014;95(3):294–306.PubMedGoogle Scholar
  88. 88.
    Giannoudis A, Davies A, Harris R, Lucas C, Pirmohamed M, Clark R. The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia. 2014;28(6):1360–3.PubMedGoogle Scholar
  89. 89.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm. 1996;24(5):475–90.PubMedGoogle Scholar
  90. 90.
    Komarova NL, Wodarz D. Effect of cellular quiescence on the success of targeted CML therapy. PLoS One. 2007;2(10):e990.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Shah K, Parikh S, Rawal R. Tyrosine kinase inhibitors in Ph+ chronic myeloid leukemia therapy: a review. Asian Pac J Cancer Prev. 2016;17(7):3025–33.PubMedGoogle Scholar
  92. 92.
    Polakova KM, Kulvait V, Benesova A, Linhartova J, Klamova H, Jaruskova M, et al. Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase. J Cancer Res Clin Oncol. 2015;141(5):887–99.Google Scholar

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Authors and Affiliations

  1. 1.Hematology, Oncology and Stem Cell Transplantation Research CenterTehran University of Medical SciencesTehranIran
  2. 2.Fred Hutchinson Cancer Research Center, Clinical Research DivisionSeattleUSA
  3. 3.Department of PathologyUniversity of WashingtonSeattleUSA

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