Tyrosine Kinase Inhibitors

  • Michael Deininger
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The extraordinary success of imatinib for the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and subgroups of patients with hypereosinophilic syndrome and chronic myelomonocytic leukemia has greatly stimulated the development of small molecule inhibitors for targeted therapy of malignant diseases. Nothing short of a major breakthrough, imatinib has undoubtedly set a precedent and provided proof of principle for a completely new concept in cancer therapy. Unfortunately, diseases other than CML may prove more resilient to targeted tyrosine kinase inhibition, and even in CML, acquired resistance is a significant clinical problem. This chapter will review the current status of tyrosine kinase inhibitors for therapy of malignant disease. Much space will be given to imatinib, as the experience gained from the development of this agent is applicable to other conditions. The emerging concept is that for the patient’s maximum therapeutic benefit, disease classifications will have to integrate therapeutic targets, and this will have implications for clinical trial design.


targeted therapy BCR-ABL FLT3 EGFR tyrosine kinase inibitors imatinib gefitinib erlotinib cancer leukemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002;298:1912–1934.PubMedCrossRefGoogle Scholar
  2. Wang Z, Shen D, Parsons DW et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 2004;304:1164–1166.PubMedCrossRefGoogle Scholar
  3. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001;411:355–365.PubMedCrossRefGoogle Scholar
  4. Nakao M, Yokota S, Iwai T et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911–1918.PubMedGoogle Scholar
  5. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813–3825.PubMedCrossRefGoogle Scholar
  6. Smith KM, Yacobi R, Van Etten RA. Autoinhibition of BCR-ABL through its SH3 domain. Mol Cell 2003;12:27–37.PubMedCrossRefGoogle Scholar
  7. Golub TR, Goga A, Barker GF et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol 1996;16:4107–4116.PubMedGoogle Scholar
  8. Reilly JT. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev 2003;17:241–248.PubMedCrossRefGoogle Scholar
  9. Ma Y, Zeng S, Metcalfe DD et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 2002;99:1741–1744.PubMedCrossRefGoogle Scholar
  10. Heinrich MC, Griffith DJ, Druker BJ et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925–932.PubMedGoogle Scholar
  11. Corbin AS, Demehri S, Griswold IJ et al. In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation loop mutants of Kit. Blood 2005;2004–2012.Google Scholar
  12. Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K. KIT exon 8 mutations associated with core binding factor (CBF) - acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood 2004;2004–2006.Google Scholar
  13. Kindler T, Breitenbuecher F, Marx A et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood 2004;103:3644–3654.PubMedCrossRefGoogle Scholar
  14. Thiede C, Steudel C, Mohr B et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002;99:4326–4335.PubMedCrossRefGoogle Scholar
  15. Griswold IJ, Shen LJ, LaRosee P et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Blood 2004;104:2912–2918.PubMedCrossRefGoogle Scholar
  16. Armstrong SA, Kung AL, Mabon ME et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003;3:173–183.PubMedCrossRefGoogle Scholar
  17. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 2002;62:3729–3735.PubMedGoogle Scholar
  18. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to Gefitinib. N Engl J Med 2004;350:2129–2139.PubMedCrossRefGoogle Scholar
  19. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.PubMedCrossRefGoogle Scholar
  20. Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–655.PubMedCrossRefGoogle Scholar
  21. Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia 2004;18:962–966.PubMedCrossRefGoogle Scholar
  22. Virchow R. Weisses Blut. Frorieps Notizen. 1845;36:151–156.Google Scholar
  23. Nowell P, Hungerford D. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497.Google Scholar
  24. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–293.PubMedCrossRefGoogle Scholar
  25. Bartram CR, de Klein A, Hagemeijer A et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983;306:277–280.PubMedCrossRefGoogle Scholar
  26. Groffen J, Stephenson JR, Heisterkamp N et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984;36:93–99.PubMedCrossRefGoogle Scholar
  27. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of BCR-ABL oncogene products. Science 1990;247:1079–1082.PubMedCrossRefGoogle Scholar
  28. Anafi M, Gazit A, Gilon C, Ben Neriah Y, Levitzki A. Selective interactions of transforming and normal abl proteins with ATP, tyrosine-copolymer substrates, and tyrphostins. J Biol Chem 1992;267:4518–4523.PubMedGoogle Scholar
  29. Anafi M, Gazit A, Zehavi A, Ben Neriah Y, Levitzki A. Tyrphostin-induced inhibition of p210BCR-ABL tyrosine kinase activity induces K562 to differentiate. Blood 1993;82:3524–3529.PubMedGoogle Scholar
  30. Zimmermann J, Buchdunger E, Mett H et al. Phenylamino-pyrimidine (PAP)-derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg Med Chem Lett 1996;6:1221–1226.CrossRefGoogle Scholar
  31. Zimmermann J, Buchdunger E, Mett H, Meyer T, Lydon NB. Potent and selective inhibitors of the Abl kinase - phenylamino-pyrimidine (PAP) derivatives. Bioorg Med Chem Lett 1997;7:187–192.Google Scholar
  32. 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
  33. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640–2653.PubMedCrossRefGoogle Scholar
  34. 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
  35. Nagar B, Bornmann WG, Pellicena P et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2002;62:4236–4243.PubMedGoogle Scholar
  36. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000;96:3343–3356.PubMedGoogle Scholar
  37. James C, Ugo V, Le Couedic JP et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.PubMedCrossRefGoogle Scholar
  38. 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
  39. Koschmieder S, Goettgens B, Zhang P et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood. 2005;105:324–334.PubMedCrossRefGoogle Scholar
  40. Wang YY, Zhou GB, Yin T et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005;102:1104–1109.PubMedCrossRefGoogle Scholar
  41. Kottaridis PD, Gale RE, Langabeer SE et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002;100:2393–2398.PubMedCrossRefGoogle Scholar
  42. 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
  43. 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
  44. Deininger M, Goldman JM, Lydon NB, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL positive cells. Blood 1997;90:3691–3698.PubMedGoogle Scholar
  45. Simonsson B for the IRIS study group. Beneficial effects of cytogenetic and molecular response on longterm outcome in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM): updata from the IRIS study [abstract]. Blood 2005;106:52a.Google Scholar
  46. Hughes TP, Deininger MW, 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
  47. Cortes J, Giles F, O’Brien S et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome–positive chronic myeloid leukemia after failure of interferon-{alpha}. Blood 2003;102:83–86.PubMedCrossRefGoogle Scholar
  48. Kantarjian HM, Talpaz M, O’Brien S et al. Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results. Clin Cancer Res 2002;8:2177–2187.PubMedGoogle Scholar
  49. Deininger MW. Management of early stage disease. Hematology Am Soc Hematol Educ Program 2005;174–182.Google Scholar
  50. 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
  51. 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;99:353–3539.CrossRefGoogle Scholar
  52. 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
  53. Schultheis B, Szydlo R, Mahon FX, Apperley JF, Melo JV. Analysis of total phosphotyrosine levels in CD34+cells from CML patients to predict the response to imatinib mesylate treatment. Blood 2005;105:4893–4894.PubMedCrossRefGoogle Scholar
  54. White D, Saunders V, Lyons AB et al. In-vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in de-novo CML patients. Blood 2005;106: 2520–2526.PubMedCrossRefGoogle Scholar
  55. Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–1537.PubMedCrossRefGoogle Scholar
  56. Blackhall F, Ranson M, Thatcher N. Where next for gefitinib in patients with lung cancer? Lancet Oncol 2006;7:499–507.PubMedCrossRefGoogle Scholar
  57. Deininger M, Schleuning M, Greinix H et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica 2006;91:452–459.PubMedGoogle Scholar
  58. Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991;65:1153–1163.PubMedCrossRefGoogle Scholar
  59. Schwartzberg PL, Stall AM, Hardin JD et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 1991;65:1165–1175.PubMedCrossRefGoogle Scholar
  60. Koleske AJ, Gifford AM, Scott ML et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 1998;21:1259–1272.PubMedCrossRefGoogle Scholar
  61. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997;277:242–245.PubMedCrossRefGoogle Scholar
  62. Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998;91:1101–1134.PubMedGoogle Scholar
  63. Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003;21:1637–1647.PubMedCrossRefGoogle Scholar
  64. Kerkela R, Grazette L, Yacobi R et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908–916.PubMedCrossRefGoogle Scholar
  65. 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
  66. Lange T, Gunther C, Kohler T et al. High levels of BAX, low levels of MRP-1, and high platelets are independent predictors of response to imatinib in myeloid blast crisis of CML. Blood 2003;101:2152–2155.PubMedCrossRefGoogle Scholar
  67. 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
  68. 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
  69. Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 2002;100:3041–3044.PubMedCrossRefGoogle Scholar
  70. 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
  71. Al Ali HK, Heinrich MC, Lange T et al. High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. Hematol J 2004;5:55–60.PubMedCrossRefGoogle Scholar
  72. 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
  73. Barthe C, Cony-Makhoul P, Melo JV, Mahon JR. Roots of clinical resistance to STI-571 cancer therapy. Science 2001;293:2163.Google Scholar
  74. Branford S, Walsh CT, Rudzki Z et al. BCR-ABL kinase domain mutations in CML patients on imatinib: incidence is correlated with duration of CML and mutations in the P-loop may be indicative of a poor outcome [abstract]. Blood 2002;100:367a.CrossRefGoogle Scholar
  75. 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
  76. Hofmann WK, Jones LC, Lemp NA et al. Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood 2002;99:1860–1862.PubMedCrossRefGoogle Scholar
  77. 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
  78. Corbin AS, Rosee PL, Stoffregen EP, Druker BJ, Deininger MW. Several BCR-ABL kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 2003;101:4611–4614.PubMedCrossRefGoogle Scholar
  79. 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
  80. La Rosee P, Johnson K, Corbin AS et al. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant BCR-ABL-positive cell lines. Blood 2004;103:208–215.PubMedCrossRefGoogle Scholar
  81. Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against BCR-ABL-positive cells. Blood 2000;96:3195–3199.PubMedGoogle Scholar
  82. La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ. 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
  83. von Bubnoff N, Veach DR, Miller WT et al. Inhibition of wild-type and mutant BCR-ABL by pyrido-pyrimidine-type small molecule kinase inhibitors. Cancer Res 2003;63:6395–6404.Google Scholar
  84. 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
  85. 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
  86. Shah N, Tran C, Lee FY, and Sawyers C. BMS-354825 is a novel orally bioavailable small molecule ABL tyrosine kinase inhibitor that successfully and safely inhibits the kinase activity of multiple imatinib-resistant BCR-ABL isoforms in vitro and in vivo [abstract]. AACR meeting 2004. 2004.Google Scholar
  87. Kimura S, Naito H, Segawa H et al. NS-187, a potent and selective dual BCR-ABL/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 2005;106:3948–3954.PubMedCrossRefGoogle Scholar
  88. 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
  89. Lombardo L, Yee F, Chen P et al. Discovery of N-(2-Chloro-6-methylphenyl)-2-(6-(4-(20hydroxyethyl)-piperazin-1-yl)-2-methylprimidin-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.PubMedCrossRefGoogle Scholar
  90. Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000;95:3498–3505.PubMedGoogle Scholar
  91. 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
  92. 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
  93. O’Hare T, Walters DK, Deininger MWN, Druker BJ. AMN101: tightening the grip of imatinib. Cancer Cell 2005;7:117–119.PubMedCrossRefGoogle Scholar
  94. Deininger MW, Druker BJ. SRCircumventing imatinib resistance. Cancer Cell 2004;6:108–110.PubMedCrossRefGoogle Scholar
  95. von Bubnoff N, Manley PW, Mestan J et al. BCR-ABL resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 2006;108:1328–1333.CrossRefGoogle Scholar
  96. Bradeen HA, Eide CA, O’Hare T et al. Comparison of imatinib, 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
  97. 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
  98. Burley S. Application of FAST TM fragment-based lead discovery and structure-guided design to discovery of small molecule inhibitors of BCR-ABL tyrosine kinase active against the T315I imatinib resistant mutant [abstract]. Proc Am Assoc Canc Res 2006;47:1139.Google Scholar
  99. Lange T, Niederwieser DW, Deininger MW. Residual disease in chronic myeloid leukemia after induction of molecular remission. N Engl J Med 2003;349:1483–1484.PubMedCrossRefGoogle Scholar
  100. Lange T, Bumm T, Mueller M et al. Durability of molecular remission in chronic myeloid leukemia patients treated with imatinib vs allogeneic stem cell transplantation. Leukemia 2005;19:1262–1265.PubMedCrossRefGoogle Scholar
  101. Deininger MW, Holyoake TL. Can we afford to let sleeping dogs lie? Blood 2005;105:1840–1841.PubMedCrossRefGoogle Scholar
  102. Cools J, DeAngelo DJ, Gotlib J et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–1214.PubMedCrossRefGoogle Scholar
  103. Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH. Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002;359:1577–1578.PubMedCrossRefGoogle Scholar
  104. Apperley JF, Gardembas M, Melo JV et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002;347:481–487.PubMedCrossRefGoogle Scholar
  105. Pardanani A, Elliott M, Reeder T et al. Imatinib for systemic mast-cell disease. Lancet 2003;362:535–536.PubMedCrossRefGoogle Scholar
  106. Pardanani A, Tefferi A. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 2004;104:1931–1939.PubMedCrossRefGoogle Scholar
  107. Tefferi A, Mesa RA, Gray LA et al. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002;99:3854–3856.PubMedCrossRefGoogle Scholar
  108. Kindler T, Breitenbuecher F, Marx A et al. Sustained complete hematologic remission after administration of the tyrosine kinase inhibitor imatinib mesylate in a patient with refractory, secondary AML. Blood 2003;101:2960–2962.PubMedCrossRefGoogle Scholar
  109. Silver RT. Imatinib mesylate (Gleevec(TM)) reduces phlebotomy requirements in polycythemia vera. Leukemia 2003;17:1186–1187.Google Scholar
  110. Jones AV, Silver RT, Waghorn K et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood 2006;107:3339–3341.PubMedCrossRefGoogle Scholar
  111. Nilsson B, Bumming P, Meis-Kindblom JM et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era. Cancer 2005;103:821–829.PubMedCrossRefGoogle Scholar
  112. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002;160: 1567–1572.PubMedGoogle Scholar
  113. Tuveson DA, Willis NA, Jacks T et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001;20:5054–5058.PubMedCrossRefGoogle Scholar
  114. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–1056.PubMedCrossRefGoogle Scholar
  115. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.PubMedCrossRefGoogle Scholar
  116. van Oosterom AT, Judson I, Verweij J et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–1423.PubMedCrossRefGoogle Scholar
  117. Heinrich MC, Corless CL, Duensing A et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–710.PubMedCrossRefGoogle Scholar
  118. Prenen H, Cools J, Mentens N et al. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 2006;12:2622–2627.PubMedCrossRefGoogle Scholar
  119. Sjoblom T, Shimizu A, O’Brien KP et al. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 2001;61:5778–5783.PubMedGoogle Scholar
  120. Rubin BP, Schuetze SM, Eary JF et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 2002;20:3586–3591.PubMedCrossRefGoogle Scholar
  121. Yamamoto Y, Kiyoi H, Nakano Y et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001;97:2434–2439.PubMedCrossRefGoogle Scholar
  122. Kelly LM, Liu Q, Kutok JL et al. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002;99:310–318.PubMedCrossRefGoogle Scholar
  123. Sohal J, Phan VT, Chan PV et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 2003;101:3188–3197.PubMedCrossRefGoogle Scholar
  124. Wadleigh M, DeAngelo DJ, Griffin JD, Stone RM. After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies. Blood 2005;105:22–30.PubMedCrossRefGoogle Scholar
  125. Heinrich MC, Druker BJ, Curtin P et al. A “first in man” study of the safety and PK/PD of an oral Flt3 inhibitor (MLN518) in patients with AML or high risk myelodysplasia. Blood 2003;100:336a.Google Scholar
  126. Fiedler W, Mesters R, Tinnefeld H et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003;102:2763–2767.PubMedCrossRefGoogle Scholar
  127. Giles FJ, Stopeck AT, Silverman LR et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003;102:795–801.PubMedCrossRefGoogle Scholar
  128. Stone RM, DeAngelo DJ, Klimek V et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:54–60.PubMedCrossRefGoogle Scholar
  129. Miyamoto T, Nagafuji K, Akashi K et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood 1996;87:4789–4796.PubMedGoogle Scholar
  130. Rusch V, Baselga J, Cordon-Cardo C et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53:2379–2385.PubMedGoogle Scholar
  131. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995;1:1311–1318.PubMedGoogle Scholar
  132. Ward WH, Cook PN, Slater AM et al. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 1994;48:659–666.PubMedCrossRefGoogle Scholar
  133. Wakeling AE, Guy SP, Woodburn JR et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002;62:5749–5754.PubMedGoogle Scholar
  134. Swaisland H, Laight A, Stafford L et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 2001;40:297–306.PubMedCrossRefGoogle Scholar
  135. Herbst RS, Maddox AM, Rothenberg ML et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002;20:3815–3825.PubMedCrossRefGoogle Scholar
  136. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002;20:2240–2250.PubMedCrossRefGoogle Scholar
  137. Baselga J, Rischin D, Ranson M et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292–4302.PubMedCrossRefGoogle Scholar
  138. Nakagawa K, Tamura T, Negoro S et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 2003;14:922–930.PubMedCrossRefGoogle Scholar
  139. Albanell J, Rojo F, Averbuch S et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2002;20:110–124.PubMedCrossRefGoogle Scholar
  140. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237–2246.PubMedCrossRefGoogle Scholar
  141. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–2158.PubMedCrossRefGoogle Scholar
  142. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol 2004;22:785–794.PubMedCrossRefGoogle Scholar
  143. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol 2004;22:777–784.PubMedCrossRefGoogle Scholar
  144. Shepherd FA, Rodrigues PJ, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.PubMedCrossRefGoogle Scholar
  145. Herbst RS, Prager D, Hermann R et al. TRIBUTE: a phase II trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–5899.PubMedCrossRefGoogle Scholar
  146. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163–1167.PubMedCrossRefGoogle Scholar
  147. Stephens P, Hunter C, Bignell G et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525–526.PubMedCrossRefGoogle Scholar
  148. Shimamura T, Ji H, Minami Y et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res 2006;66:6487–6491.PubMedCrossRefGoogle Scholar
  149. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792.PubMedCrossRefGoogle Scholar
  150. 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
  151. Kwak EL, Sordella R, Bell DW et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005;102:7665–7670.PubMedCrossRefGoogle Scholar
  152. Kobayashi S, Ji H, Yuza Y et al. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res 2005;65:7096–7101.PubMedCrossRefGoogle Scholar
  153. Bardelli A, Parsons DW, Silliman N et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003;300:949.Google Scholar
  154. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954.PubMedCrossRefGoogle Scholar
  155. Samuels Y, Wang Z, Bardelli A et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.Google Scholar
  156. Baxter EJ, Scott LM, Campbell PJ et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–1061.PubMedGoogle Scholar
  157. Levine RL, Wadleigh M, Cools J et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387–397.PubMedCrossRefGoogle Scholar
  158. Mesa RA, Li CY, Ketterling RP et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single institution experience with 91 cases. Blood 2005;105:973–977.PubMedCrossRefGoogle Scholar
  159. Shah NP, Tran C, Lee FY et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.PubMedCrossRefGoogle Scholar
  160. Lee FY, Lombardo L, Borzilleri R et al. BMS-354825 - a potent SRC/ABL kinase inhibitor possessing curative efficacy against imatinib sensitive and resistant human CML models in vivo [abstract]. AACR meeting 2004. 2004.Google Scholar
  161. Smith BD, Levis M, Beran M et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004;103:3669–3676.PubMedCrossRefGoogle Scholar
  162. Kelly LM, Yu JC, Boulton CL et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 2002;1:421–432.PubMedCrossRefGoogle Scholar
  163. Fiedler W, Serve H, Dohner H et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005;105:986-993.Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Michael Deininger

There are no affiliations available

Personalised recommendations