Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML)

Critical Reviews in Oncology/Hematology

Volumn 57, Issue 2, 2006, Pages 145-164

  Walz, Christoph ^a,c   Sattler, Martin ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

BCR ABL; Chronic myeloid leukemia; Imatinib mesylate; Resistance; Tyrosine kinase inhibitor

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 2 MORPHOLINO 8 PHENYLCHROMONE; ABELSON KINASE; AP 23573; BCR ABL PROTEIN; BMS 345825; CELECOXIB; DASATINIB; EVEROLIMUS; IMATINIB; NILOTINIB; ON 012380; OSU 03012; RAPAMYCIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; WORTMANNIN;

CHRONIC MYELOID LEUKEMIA; DRUG ACTIVITY; DRUG BINDING; DRUG EFFECT; DRUG MECHANISM; DRUG POTENCY; DRUG RESISTANCE; DRUG SENSITIVITY; DRUG TARGETING; ENZYME ACTIVITY; ENZYME BINDING; ENZYME INHIBITION; ENZYME STABILITY; FUSION GENE; GENE AMPLIFICATION; GENOMIC INSTABILITY; HEMATOPOIETIC STEM CELL; HUMAN; POINT MUTATION; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; HUMANS; LEUKEMIA, MYELOID, CHRONIC; PIPERAZINES; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PYRIMIDINES;

EID: 31344472945     PISSN: 10408428     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2005.06.007     Document Type: Review

References (200)

1. P.C. Nowell, and D.A. Hungerford Chromosome studies on normal and leukemic human leukocytes J Natl Cancer Inst 25 1960 85 109
2. J.D. Rowley Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining Nature 243 1973 290 293
3. N. Heisterkamp, J.R. Stephenson, and J. Groffen Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia Nature 306 1983 239 242
4. M. Sattler, and J.D. Griffin Molecular mechanisms of transformation by the BCR-ABL oncogene Semin Hematol 40 2003 4 10
5. E. Fainstein, C. Marcelle, and A. Rosner A new fused transcript in Philadelphia chromosome positive acute lymphocytic leukaemia Nature 330 1987 386 388
6. G. Saglio, A. Guerrasio, and C. Rosso New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia Blood 76 1990 1819 1824
7. H. Wada, S. Mizutani, and J. Nishimura Establishment and molecular characterization of a novel leukemic cell line with Philadelphia chromosome expressing p230 BCR/ABL fusion protein Cancer Res 55 1995 3192 3196
8. J.V. Melo The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype Blood 88 1996 2375 2384
9. M. Azam, R.R. Latek, and G.Q. Daley Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL Cell 112 2003 831 843
10. O. Hantschel, B. Nagar, and S. Guettler A myristoyl/phosphotyrosine switch regulates c-Abl Cell 112 2003 845 857
11. B. Nagar, O. Hantschel, and M.A. Young Structural basis for the autoinhibition of c-Abl tyrosine kinase Cell 112 2003 859 871
12. J.B. Konopka, S.M. Watanabe, and O.N. Witte An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity Cell 37 1984 1035 1042
13. C.A. Evans, P.J. Owen-Lynch, A.D. Whetton, and C. Dive Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells Cancer Res 53 1993 1735 1738
14. B.J. Druker, S. Tamura, and E. Buchdunger Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells Nat Med 2 1996 561 566
15. E. Buchdunger, J. Zimmermann, and H. Mett Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 56 1996 100 104
16. E. Buchdunger, C.L. Cioffi, and N. Law Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors J Pharmacol Exp Ther 295 2000 139 145
17. T. Schindler, W. Bornmann, P. Pellicena, W.T. Miller, B. Clarkson, and J. Kuriyan Structural mechanism for STI-571 inhibition of abelson tyrosine kinase Science 289 2000 1938 1942
18. C. Gambacorti-Passerini, C.P. Le, and L. Mologni Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis Blood Cells Mol Dis 23 1997 380 394
19. M.W. Deininger, J.M. Goldman, N. Lydon, and J.V. Melo The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells Blood 90 1997 3691 3698
20. C.L. Sawyers, A. Hochhaus, and E. Feldman Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study Blood 99 2002 3530 3539
21. U. Berger, G. Engelich, A. Reiter, A. Hochhaus, and R. Hehlmann Imatinib and beyond - the new CML study. IV. A randomized controlled comparison of imatinib vs imatinib/interferon-alpha vs imatinib/low-dose AraC vs imatinib after interferon-alpha failure in newly diagnosed chronic phase chronic myeloid leukemia Ann Hematol 83 2004 258 264
22. B.J. Druker, M. Talpaz, and D.J. Resta Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 344 2001 1031 1037
23. J.M. Goldman, and B.J. Druker Chronic myeloid leukemia: current treatment options Blood 98 2001 2039 2042
24. M.H. Cohen, G. Williams, and J.R. Johnson Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia Clin Cancer Res 8 2002 935 942
25. S.G. O'Brien, P. Meinhardt, and E. Bond Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia Br J Cancer 89 2003 1855 1859
26. M.C. Heinrich, D.J. Griffith, B.J. Druker, C.L. Wait, K.A. Ott, and A.J. Zigler Inhibition of c-kit receptor tyrosine kinase activity by STI571, a selective tyrosine kinase inhibitor Blood 96 2000 925 932
27. J. Cools, D.J. DeAngelo, and J. Gotlib 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 348 2003 1201 1214
28. S. Roumiantsev, N.P. Shah, and M.E. Gorre Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop Proc Natl Acad Sci USA 99 2002 10700 10705
29. M. Sattler, and R. Salgia Targeting c-kit mutations: basic science to novel therapies Leuk Res 28 Suppl 1 2004 S11 S20
30. P. Valent, C. Akin, and W.R. Sperr Mastocytosis: pathology, genetics, and current options for therapy Leuk Lymphoma 46 2005 35 48
31. M.J. Frost, P.T. Ferrao, T.P. Hughes, and L.K. Ashman Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant Mol Cancer Ther 1 2002 1115 1124
32. C. James, V. Ugo, and J.P. Le Couedic A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera Nature 434 2005 1144 1148
33. R. Kralovics, F. Passamonti, and A.S. Buser A gain-of-function mutation of JAK2 in myeloproliferative disorders N Engl J Med 352 2005 1779 1790
34. R.L. Levine, M. Wadleigh, and J. Cools Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis Cancer Cell 7 2005 387 397
35. E.J. Baxter, L.M. Scott, and P.J. Campbell Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders Lancet 365 2005 1054 1061
36. R. Zhao, S. Xing, and Z. Li Identification of an acquired JAK2 mutation in polycythemia vera J Biol Chem 280 2005 22788 22792
37. T.L. Holyoake, X. Jiang, and H.G. Jorgensen Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3 Blood 97 2001 720 728
38. R. Bhatia, M. Holtz, and N. Niu Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment Blood 101 2003 4701 4707
39. O.G. Ottmann, B.J. Druker, and C.L. Sawyers A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias Blood 100 2002 1965 1971
40. Gambacorti-Passerini C, BS, Cazzaniga G. BCR-ABL gene amplification causes reversible cytogenetic relapse and resistance to imatinib (STI571) in a chronic phase CML patients. Blood 2002;100:216a.
41. J.Y. Wang, F. Ledley, S. Goff, R. Lee, Y. Groner, and D. Baltimore The mouse c-abl locus: molecular cloning and characterization Cell 36 1984 349 356
42. R.A. Van Etten Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era Leuk Res 28 Suppl 1 2004 S21 S28
43. B.B. Brasher, S. Roumiantsev, and R.A. Van Etten Mutational analysis of the regulatory function of the c-Abl Src homology 3 domain Oncogene 20 2001 7744 7752
44. B.B. Brasher, and R.A. Van Etten 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 275 2000 35631 35637
45. B. Nagar, W.G. Bornmann, and P. Pellicena Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571) Cancer Res 62 2002 4236 4243
46. M.E. Gorre, M. Mohammed, and K. Ellwood Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 293 2001 876 880
47. A. Hochhaus, S. Kreil, and A.S. Corbin Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy Leukemia 16 2002 2190 2196
48. N.P. Shah, J.M. Nicoll, and B. Nagar 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 2 2002 117 125
49. S. Branford, Z. Rudzki, and S. Walsh High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance Blood 99 2002 3472 3475
50. S. Branford, Z. Rudzki, and S. Walsh 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 102 2003 276 283
51. C. Roche-Lestienne, and C. Preudhomme Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment Semin Hematol 40 2003 80 82
52. N. von Bubnoff, F. Schneller, C. Peschel, and J. Duyster BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study Lancet 359 2002 487 491
53. A. Hochhaus, S. Kreil, and A. Corbin Roots of clinical resistance to STI-571 cancer therapy Science 293 2001 2163
54. W.K. Hofmann, L.C. Jones, and N.A. Lemp Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation Blood 99 2002 1860 1862
55. S.W. Cowan-Jacob, V. Guez, and G. Fendrich Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment Mini Rev Med Chem 4 2004 285 299
56. T. Tauchi, and K. Ohyashiki Molecular mechanisms of resistance of leukemia to imatinib mesylate Leuk Res 28 Suppl 1 2004 S39 S45
57. K.Q. Tanis, D. Veach, H.S. Duewel, W.G. Bornmann, and A.J. Koleske Two distinct phosphorylation pathways have additive effects on Abl family kinase activation Mol Cell Biol 23 2003 3884 3896
58. P. Le Coutre, E. Tassi, and M. Varella-Garcia Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification Blood 95 2000 1758 1766
59. S. Kreil, M.C. Muller, and T. Lahaye Molecular and chromosomal mechanisms of resistance in CML patients after STI571 (Glivec) therapy Blood 98 2001 435a
60. A. Hochhaus, and R.P. La Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance Leukemia 18 2004 1321 1331
61. A. Hamada, H. Miyano, H. Watanabe, and H. Saito Interaction of imatinib mesilate with human P-glycoprotein J Pharmacol Exp Ther 307 2003 824 828
62. N. Widmer, S. Colombo, T. Buclin, and L.A. Decosterd Functional consequence of MDR1 expression on imatinib intracellular concentrations Blood 102 2003 1142
63. T. Hegedus, L. Orfi, A. Seprodi, A. Varadi, B. Sarkadi, and G. Keri Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1 Biochim Biophys Acta 1587 2002 318 325
64. F.X. Mahon, M.W. Deininger, and B. Schultheis Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance Blood 96 2000 1070 1079
65. F.X. Mahon, F. Belloc, and V. Lagarde MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models Blood 101 2003 2368 2373
66. P.T. Ferrao, M.J. Frost, S.P. Siah, and L.K. Ashman Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro Blood 102 2003 4499 4503
67. C. Gambacorti-Passerini, R. Barni, and C.P. Le 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 92 2000 1641 1650
68. F. Staud, and P. Pavek Breast cancer resistance protein (BCRP/ABCG2) Int J BioChem Cell Biol 37 2005 720 725
69. P.J. Houghton, G.S. Germain, and F.C. Harwood Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro Cancer Res 64 2004 2333 2337
70. H. Burger, T.H. van, and A.W. Boersma Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump Blood 104 2004 2940 2942
71. M. Sattler, S. Verma, and G. Shrikhande The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells J Biol Chem 275 2000 24273 24278
72. Y.A. Suh, R.S. Arnold, and B. Lassegue Cell transformation by the superoxide-generating oxidase Mox1 Nature 401 1999 79 82
73. D. Dreher, and A.F. Junod Role of oxygen free radicals in cancer development Eur J Cancer 32A 1996 30 38
74. M.O. Nowicki, R. Falinski, and M. Koptyra BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks Blood 104 2004 3746 3753
75. E. Weisberg, P.W. Manley, and W. Breitenstein Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 7 2005 129 141
76. M. Sattler, M.G. Mohi, and Y.B. Pride Critical role for Gab2 in transformation by BCR/ABL Cancer Cell 1 2002 479 492
77. G. Martinelli, A.M. Martelli, and T. Grafone A new Abl kinase inhibitor (AMN107) has in vitro activity on CML Ph+ blast cells resistant to imatinib Blood 104 2004 255
78. F.X. Mahon, V. Lagarde, P.W. Manley, J.M. Pasquet, B. Turcq, and J. Reiffers Generation of resistance cell lines to AMN107, a new inhibitor of BCR-ABL and its effects on cell lines sensitive and resistant to imatinib Blood 104 2004 253b
79. P. Le Coutre, G. Baskaynak, and I. Tamm Activity and induction of apoptosis of the specific tyrosine kinase inhibitor AMN 107 in bcr-abl+ cell lines and in imatinib resistant primary cells from CML patients Blood 104 2004 218a
80. K. Pietras Increasing tumor uptake of anticancer drugs with imatinib Semin Oncol 31 2004 18 23
81. F. Giles, H.M. Kantarjian, and B. Wassmann A phase I/II study of AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, on a continuous daily dosing schedule in adult patients (pts) with imatinib-resistant advanced phase chronic myeloid leukemia (CML) or relapsed/refractory Philadelphia chromosome (Ph+) acute llymphocytic leukemia (ALL) Blood 104 2005 10a
82. N.P. Shah, C. Tran, F.Y. Lee, P. Chen, D. Norris, and C.L. Sawyers Overriding imatinib resistance with a novel ABL kinase inhibitor Science 305 2004 399 401
83. J. Tokarski, J. Newitt, and F.Y. Lee The Crystal structure of Abl kinase with BMS-354825, a dual SRC/ABL kinase inhibitor Blood 104 2004 160a
84. L.J. Lombardo, F.Y. Lee, and P. Chen Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays J Med Chem 47 2004 6658 6661
85. M. Schittenhelm, S. Shiraga, F.Y. Lee, and M.C. Heinrich BMS-354825 potently inhibits the kinase activity of KIT activation loop mutations associated with systemic mastocytosis and induces apoptosis of mastocytosis cell lines Blood 104 2004 666a
86. C.L. Sawyers, N.P. Shah, and H.M. Kantarjian Hematologic and cytogenetic responses in imatinib-resistant chronic phase chronic myeloid leukemia patients treated with the dual SRC/ABL kinase inhibitor BMS-354825: results from a phase I dose escalation study Blood 104 2004 10a
87. M.R. Burgess, N.P. Shah, B.J. Skaggs, F.Y. Lee, and T.K. Sawyer Comparative analysis of two BCR-ABL small molecule inhibitors reveals overlapping but distinct mechanisms of resistance Blood 104 2004 552a
88. S. Branford, Z. Rudzki, and A. Harper Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase Leukemia 17 2003 2401 2409
89. N.P. Shah, S. Branford, T. Hughes, J. Nicoll, A.P. DeCillis, and T.K. Sawyer Major cytogenetic responses to BMS-354825 in patients with chronic myeloid leukemia are associated with a one to two log reduction in BCR-ABL transcript Blood 104 2004 288a
90. K. Gumireddy, S.J. Baker, and S.C. Cosenza A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance Proc Natl Acad Sci USA 102 2005 1992 1997
91. S. Danhauser-Riedl, M. Warmuth, B.J. Druker, B. Emmerich, and M. Hallek Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells Cancer Res 56 1996 3589 3596
92. J.M. Lionberger, M.B. Wilson, and T.E. Smithgall Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck J Biol Chem 275 2000 18581 18585
93. S. Ghaffari, H. Wu, M. Gerlach, Y. Han, H.F. Lodish, and G.Q. Daley BCR-ABL and v-SRC tyrosine kinase oncoproteins support normal erythroid development in erythropoietin receptor-deficient progenitor cells Proc Natl Acad Sci USA 96 1999 13186 13190
94. Y. Hu, Y. Liu, and S. Pelletier Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia Nat Genet 36 2004 453 461
95. M.V. Yezhelyev, G. Koehl, and M. Guba Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice Clin Cancer Res 10 2004 8028 8036
96. D.D. Boyd, H. Wang, and H. Avila Combination of an SRC kinase inhibitor with a novel pharmacological antagonist of the urokinase receptor diminishes in vitro colon cancer invasiveness Clin Cancer Res 10 2004 1545 1555
97. W.C. Shakespeare, C.A. Metcalf III, and Y. Wang Novel bone-targeted Src tyrosine kinase inhibitor drug discovery Curr Opin Drug Discov Dev 6 2003 729 741
98. N.C. Wolff, D.R. Veach, W.P. Tong, W.G. Bornmann, B. Clarkson, and R.L. Ilaria PD166326, a novel tyrosine kinase inhibitor, has greater anti-leukemic activity than imatinib in a murine model of chronic myeloid leukemia Blood 105 2005 3995 4003
99. Y. Liu, A. Bishop, and L. Witucki Structural basis for selective inhibition of Src family kinases by PP1 Chem Biol 6 1999 671 678
100. M. Warmuth, N. Simon, and O. Mitina Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases Blood 101 2003 664 672
101. J.H. Hanke, J.P. Gardner, and R.L. Dow Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation J Biol Chem 271 1996 695 701
102. M. Missbach, M. Jeschke, and J. Feyen A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo Bone 24 1999 437 449
103. J.M. Hamby, C.J. Connolly, and M.C. Schroeder Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors J Med Chem 40 1997 2296 2303
104. D.H. Boschelli, Z. Wu, and S.R. Klutchko Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8H-pyrido[2,3-d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors J Med Chem 41 1998 4365 4377
105. A.J. Kraker, B.G. Hartl, A.M. Amar, M.R. Barvian, H.D. Showalter, and C.W. Moore Biochemical and cellular effects of c-Src kinase-selective pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors BioChem Pharmacol 60 2000 885 898
106. J.F. Dorsey, R. Jove, A.J. Kraker, and J. Wu The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells Cancer Res 60 2000 3127 3131
107. M. Huang, J.F. Dorsey, and P.K. Epling-Burnette Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells Oncogene 21 2002 8804 8816
108. D. Wisniewski, C.L. Lambek, and C. Liu Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases Cancer Res 62 2002 4244 4255
109. N.J. Donato, J.Y. Wu, and J. Stapley BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571 Blood 101 2003 690 698
110. Y. Dai, M. Rahmani, S.J. Corey, P. Dent, and S. Grant A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2 J Biol Chem 279 2004 34227 34239
111. J.L. Bos Ras oncogenes in human cancer: a review Cancer Res 49 1989 4682 4689
112. D.M. Beaupre, and R. Kurzrock RAS and leukemia: from basic mechanisms to gene-directed therapy J Clin Oncol 17 1999 1071 1079
113. T. Skorski, P. Kanakaraj, and D.H. Ku Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth J Exp Med 179 1994 1855 1865
114. A.M. Pendergast, L.A. Quilliam, and L.D. Cripe BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein Cell 75 1993 175 185
115. L. Puil, J. Liu, and G. Gish Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway EMBO J 13 1994 764 773
116. D. Cortez, L. Kadlec, and A.M. Pendergast Structural and signaling requirements for BCR-ABL-mediated transformation and inhibition of apoptosis Mol Cell Biol 15 1995 5531 5541
117. B. Druker, K. Okuda, U. Matulonis, R. Salgia, T. Roberts, and J.D. Griffin Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines Blood 79 1992 2215 2220
118. K. Kato, A.D. Cox, M.M. Hisaka, S.M. Graham, J.E. Buss, and C.J. Der Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity Proc Natl Acad Sci USA 89 1992 6403 6407
119. G.C. Prendergast, and N. Rane Farnesyltransferase inhibitors: mechanism and applications Expert Opin Invest Drugs 10 2001 2105 2116
120. D.W. End Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway Invest New Drugs 17 1999 241 258
121. F. Caponigro, M. Casale, and J. Bryce Farnesyl transferase inhibitors in clinical development Expert Opin Invest Drugs 12 2003 943 954
122. H.R. Ashar, L. James, and K. Gray Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules J Biol Chem 275 2000 30451 30457
123. E.K. Rowinsky, J.J. Windle, and D.D. Von Hoff Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development J Clin Oncol 17 1999 3631 3652
124. G.C. Prendergast Farnesyltransferase inhibitors define a role for RhoB in controlling neoplastic pathophysiology Histol Histopathol 16 2001 269 275
125. J.E. Lancet, and J.E. Karp Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy Blood 102 2003 3880 3889
126. R. Kurzrock, M. Albitar, and J.E. Cortes Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome J Clin Oncol 22 2004 1287 1292
127. J.E. Karp Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies Semin Hematol 38 2001 16 23
128. J. Cortes, M. Albitar, and D. Thomas Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies Blood 101 2003 1692 1697
129. P.N. Lara Jr., L.Y. Law, and J.J. Wright Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial Anticancer Drugs 16 2005 317 321
130. T. Miyoshi, T. Nagai, and K. Ohmine Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines BioChem Pharmacol 69 2005 1585 1594
131. F.R. Khuri, B.S. Glisson, and E.S. Kim Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors Clin Cancer Res 10 2004 2968 2976
132. J.S. de Bono, A.W. Tolcher, and E.K. Rowinsky Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma Semin Oncol 30 2003 79 92
133. R.R. Hoover, F.X. Mahon, J.V. Melo, and G.Q. Daley Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336 Blood 100 2002 1068 1071
134. V. Manne, F.Y. Lee, and D.K. Bol Apoptotic and cytostatic farnesyltransferase inhibitors have distinct pharmacology and efficacy profiles in tumor models Cancer Res 64 2004 3974 3980
135. H.J. Mackay, R. Hoekstra, and F.A. Eskens A phase I pharmacokinetic and pharmacodynamic study of the farnesyl transferase inhibitor BMS-214662 in combination with cisplatin in patients with advanced solid tumors Clin Cancer Res 10 2004 2636 2644
136. G.K. Dy, L.M. Bruzek, and G.A. Croghan A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer Clin Cancer Res 11 2005 1877 1883
137. J.A. James, M.A. Smith, and E.L. Court An investigation of the effects of the MEK inhibitor U0126 on apoptosis in acute leukemia Hematol J 4 2003 427 432
138. C.D. Kang, S.D. Yoo, and B.W. Hwang The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells Leuk Res 24 2000 527 534
139. C. Yu, G. Krystal, and L. Varticovksi Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells Cancer Res 62 2002 188 199
140. A. Toker Protein kinases as mediators of phosphoinositide 3-kinase signaling Mol Pharmacol 57 2000 652 658
141. L.E. Rameh, and L.C. Cantley The role of phosphoinositide 3-kinase lipid products in cell function J Biol Chem 274 1999 8347 8350
142. T. Skorski, P. Kanakaraj, and M. Nieborowska-Skorska Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells Blood 86 1995 726 736
143. M. Sattler, R. Salgia, and K. Okuda The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3′ kinase pathway Oncogene 12 1996 839 846
144. L. Varticovski, G.Q. Daley, P. Jackson, D. Baltimore, and L.C. Cantley Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants Mol Cell Biol 11 1991 1107 1113
145. J.H. Kim, S.C. Chu, and J.L. Gramlich Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species Blood 2004
146. S. Zhao, M. Konopleva, and M. Cabreira-Hansen Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias Leukemia 18 2004 267 275
147. A. Klejman, L. Rushen, A. Morrione, A. Slupianek, and T. Skorski Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571 Oncogene 21 2002 5868 5876
148. S.B. Marley, J.L. Lewis, H. Schneider, C.E. Rudd, and M.Y. Gordon Phosphatidylinositol-3 kinase inhibitors reproduce the selective antiproliferative effects of imatinib on chronic myeloid leukaemia progenitor cells Br J Haematol 125 2004 500 511
149. P.H. Tseng, H.P. Lin, and J. Zhu Synergistic interactions between imatinib and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib resistance Blood 105 2005 4021 4027
150. J. Zhu, J.W. Huang, and P.H. Tseng From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors Cancer Res 64 2004 4309 4318
151. A. Panwalkar, S. Verstovsek, and F.J. Giles Mammalian target of rapamycin inhibition as therapy for hematologic malignancies Cancer 100 2004 657 666
152. C. Ly, A.F. Arechiga, J.V. Melo, C.M. Walsh, and S.T. Ong Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin Cancer Res 63 2003 5716 5722
153. S. Huang, and P.J. Houghton Targeting mTOR signaling for cancer therapy Curr Opin Pharmacol 3 2003 371 377
154. M.G. Mohi, C. Boulton, and T.L. Gu Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs Proc Natl Acad Sci USA 101 2004 3130 3135
155. M. Sattler, L.R. Quinnan, and Y.B. Pride 2-Methoxyestradiol alters cell motility, migration, and adhesion Blood 102 2003 289 296
156. M. Groll, and R. Huber Inhibitors of the eukaryotic 20S proteasome core particle: a structural approach Biochim Biophys Acta 1695 2004 33 44
157. Y. Dai, M. Rahmani, X.Y. Pei, P. Dent, and S. Grant Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Blood 104 2004 509 518
158. M.J. Peart, G.K. Smyth, and R.K. van Laar Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors Proc Natl Acad Sci USA 102 2005 3697 3702
159. Y. Xu, S. Voelter-Mahlknecht, and U. Mahlknecht The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell lines Int J Mol Med 15 2005 169 172
160. P. La Rosee, K. Johnson, and A.S. Corbin In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines Blood 103 2004 208 215
161. L.M. Angerer, and R.C. Angerer Disruption of gene function using antisense morpholinos Meth Cell Biol 74 2004 699 711
162. T. Skorski, M. Nieborowska-Skorska, and N.C. Nicolaides Suppression of Philadelphia1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide Proc Natl Acad Sci USA 91 1994 4504 4508
163. S. Dhut, T. Chaplin, and B.D. Young BCR-ABL and BCR proteins: biochemical characterization and localization Leukemia 4 1990 745 750
164. M. Scherr, K. Battmer, T. Winkler, O. Heidenreich, A. Ganser, and M. Eder Specific inhibition of bcr-abl gene expression by small interfering RNA Blood 101 2003 1566 1569
165. L.J. Scherer, and J.J. Rossi Approaches for the sequence-specific knockdown of mRNA Nat Biotechnol 21 2003 1457 1465
166. C.P. Shelburne, and T.F. Huff Inhibition of kit expression in P815 mouse mastocytoma cells by a hammerhead ribozyme Clin Immunol 93 1999 46 58
167. Y.A. Zhang, J. Nemunaitis, and A.W. Tong Generation of a ribozyme-adenoviral vector against K-ras mutant human lung cancer cells Mol Biotechnol 15 2000 39 49
168. D.S. Snyder, Y. Wu, and J.L. Wang Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia chromosome-positive cell line Blood 82 1993 600 605
169. A. Carrello, R.K. Allan, and S.L. Morgan Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70 Cell Stress Chaperones 9 2004 167 181
170. L.F. Stancato, A.M. Silverstein, J.K. Owens-Grillo, Y.H. Chow, R. Jove, and W.B. Pratt The hsp90-binding antibiotic geldanamycin decreases Raf levels and epidermal growth factor signaling without disrupting formation of signaling complexes or reducing the specific enzymatic activity of Raf kinase J Biol Chem 272 1997 4013 4020
171. C. Schneider, L. Sepp-Lorenzino, and E. Nimmesgern Pharmacologic shifting of a balance between protein refolding and degradation mediated by Hsp90 Proc Natl Acad Sci USA 93 1996 14536 14541
172. R. Nimmanapalli, E. O'Bryan, and K. Bhalla Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts Cancer Res 61 2001 1799 1804
173. M.E. Gorre, K. Ellwood-Yen, G. Chiosis, N. Rosen, and C.L. Sawyers 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 100 2002 3041 3044
174. A. Radujkovic, M. Schad, and J. Topaly Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR Leukemia 2005
175. J. Topaly, M. Schad, S. Laufs, J.V. Melo, W.J. Zeller, and S. Fruehauf Cross-resistance of imatinib mesylate and 17-AAG in imatinib-resistant cells that overexpress BCR-ABL Br J Haematol 121 2003 672 673
176. M.W. Deininger, and B.J. Druker SRCircumventing imatinib resistance Cancer Cell 6 2004 108 110
177. T. Hughes, and S. Branford Molecular monitoring of chronic myeloid leukemia Semin Hematol 40 2003 62 68
178. P. Andreasson, B. Johansson, and M. Carlsson BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion Genes Chromosomes Cancer 20 1997 299 304
179. S. Xiao, S.R. Nalabolu, and J.C. Aster FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome Nat Genet 18 1998 84 87
180. C. Popovici, B. Zhang, and M.J. Gregoire The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1 Blood 93 1999 1381 1389
181. G. Guasch, G.J. Mack, and C. Popovici FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33) Blood 95 2000 1788 1796
182. A. Demiroglu, E.J. Steer, and C. Heath The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins Blood 98 2001 3778 3783
183. E. Belloni, M. Trubia, and P. Gasparini 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes Genes Chromosomes Cancer 42 2005 320 325
184. E.K. Grand, F.H. Grand, and A.J. Chase Identification of a novel gene, FGFR1OP2, fused to FGFR1 in the 8p11 myeloproliferative syndrome Genes Chromosomes Cancer 40 2003 78 83
185. C. Walz, A. Chase, and C. Schoch The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1 Leukemia 19 2005 1005 1009
186. G. Guasch, C. Popovici, and F. Mugneret Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3) Blood 101 2003 286 288
187. P. Peeters, S.D. Raynaud, and J. Cools Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia Blood 90 1997 2535 2540
188. A. Reiter, C. Walz, and A. Watmore The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2 Cancer Res 65 2005 2662 2667
189. Y. Kuno, A. Abe, and N. Emi Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12) Blood 97 2001 1050 1055
190. E.J. Baxter, A. Hochhaus, and P. Bolufer The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA Hum Mol Genet 11 2002 1391 1397
191. T.R. Golub, G.F. Barker, M. Lovett, and D.G. Gilliland Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation Cell 77 1994 307 316
192. T.S. Ross, O.A. Bernard, R. Berger, and D.G. Gilliland Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2) Blood 91 1998 4419 4426
193. S. Kulkarni, C. Heath, and S. Parker Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21) Cancer Res 60 2000 3592 3598
194. M.K. Magnusson, K.E. Meade, and K.E. Brown Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia Blood 98 2001 2518 2525
195. K. Wilkinson, E.R. Velloso, and L.F. Lopes Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib Blood 102 2003 4187 4190
196. C. Morerio, M. Acquila, and C. Rosanda HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2) Cancer Res 64 2004 2649 2651
197. J.L. Vizmanos, F.J. Novo, and J.P. Roman NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder Cancer Res 64 2004 2673 2676
198. F.H. Grand, S. Burgstaller, and T. Kuhr p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder Cancer Res 64 2004 7216 7219
199. R.L. Levine, M. Wadleigh, and D.W. Sternberg KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32) Leukemia 19 2005 27 30
200. M.R. Burgess, B.J. Skaggs, N.P. Shah, F.Y. Lee, and C.L. Sawyers Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance Proc Natl Acad Sci USA 102 2005 3395 3400