Skip to main content

Advertisement

SpringerLink
Log in

The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias

  • REVIEW ARTICLE
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Chronic myeloid leukemia (CML) was the first human malignant disease to be linked to a single, acquired genetic abnormality. Identification of the Bcr-Abl kinase fusion protein and its pivotal role in the pathogenesis of CML provided new opportunities to develop molecular-targeted therapies. Imatinib mesylate (IM, Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), which specifically inhibits the autophosphorylation of the Abl TK, has improved the treatment of CML. However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Inhibitors of Abl TK are divided into two main groups, namely, ATP-competitive and ATP noncompetitive inhibitors. The ATP-competitive inhibitors fall into two subclasses, the Src/Abl inhibitors, and the 2-phenylaminopyrimidine-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606, and PD166326 are classified as Src/Abl inhibitors, while nilotinib (AMN107) and INNO-406 (NS-187) belong to the latter subclass of inhibitors. Of these agents, dasatinib and nilotinib underwent clinical trials earlier than the others and favorable results are now accumulating. Clinical studies of the other compounds, including SKI-606 and INNO-406, have been performed in rapid succession. Because of their strong affinities for the ATP-binding site compared to IM, most ATP-competitive inhibitors may be effective in IM-resistant patients. However, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. Instead, ATP noncompetitive inhibitors, such as ON012380, Aurora kinase inhibitor MK0457 (VX-680), and p38 MAP kinase inhibitor BIRB-796, have been developed to address this problem. This review provides an update on the underlying pathophysiologies of disease progression and IM resistance, and discusses the development of new targeted TK inhibitors for managing CML and the importance of future strategies targeting CML stem cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. S Faderl M Talpaz Z Estrov et al. (1999) ArticleTitleChronic myelogenous leukemia: biology and therapy Ann Intern Med 131 207–219 Occurrence Handle10428738 Occurrence Handle1:STN:280:DyaK1MzktlaisA%3D%3D

    PubMed  CAS  Google Scholar 

  2. JM Goldman JV Melo (2003) ArticleTitleChronic myeloid leukemia – advances in biology and new approaches to treatment N Engl J Med 349 1451–1464 Occurrence Handle14534339 Occurrence Handle1:CAS:528:DC%2BD3sXotVGgsLc%3D Occurrence Handle10.1056/NEJMra020777

    Article  PubMed  CAS  Google Scholar 

  3. JD Rowley (1973) ArticleTitleA new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining Nature 243 290–293 Occurrence Handle4126434 Occurrence Handle1:STN:280:DyaE2c%2Fgs1eksw%3D%3D Occurrence Handle10.1038/243290a0

    Article  PubMed  CAS  Google Scholar 

  4. N Heisterkamp JR Stephenson J Groffen et al. (1983) ArticleTitleLocalization of the c-Abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia Nature 306 239–242 Occurrence Handle6316147 Occurrence Handle1:CAS:528:DyaL2cXhvVKrsQ%3D%3D Occurrence Handle10.1038/306239a0

    Article  PubMed  CAS  Google Scholar 

  5. R Kurzrock JU Gutterman M Talpaz (1988) ArticleTitleThe molecular genetics of Philadelphia chromosome-positive leukemias N Engl J Med 319 990–998 Occurrence Handle3047582 Occurrence Handle1:CAS:528:DyaL1cXmt1ensbs%3D Occurrence Handle10.1056/NEJM198810133191506

    Article  PubMed  CAS  Google Scholar 

  6. TG Lugo AM Pendergast AJ Muller ON Witte (1990) ArticleTitleTyrosine kinase activity and transformation potency of Bcr-Abl oncogene products Science 247 1079–1082 Occurrence Handle2408149 Occurrence Handle1:CAS:528:DyaK3cXhslensbg%3D Occurrence Handle10.1126/science.2408149

    Article  PubMed  CAS  Google Scholar 

  7. CL Sawyers (1999) ArticleTitleChronic myeloid leukemia N Engl J Med 340 1330–1340 Occurrence Handle10219069 Occurrence Handle1:STN:280:DyaK1M3hvFOlug%3D%3D Occurrence Handle10.1056/NEJM199904293401706

    Article  PubMed  CAS  Google Scholar 

  8. E Fainstein C Marcelle A Rosner et al. (1987) ArticleTitleA new fused transcript in Philadelphia chromosome positive acute lymphocytic leukaemia Nature 330 386–388 Occurrence Handle2825022 Occurrence Handle1:CAS:528:DyaL1cXjt12kuw%3D%3D Occurrence Handle10.1038/330386a0

    Article  PubMed  CAS  Google Scholar 

  9. M Sattler JD Griffin (2003) ArticleTitleMolecular mechanisms of transformation by the Bcr-Abl oncogene Semin Hematol 40 4–10 Occurrence Handle12783368 Occurrence Handle1:CAS:528:DC%2BD3sXlt1yrtbw%3D Occurrence Handle10.1053/shem.2003.50034

    Article  PubMed  CAS  Google Scholar 

  10. H Wada S Mizutani J Nishimura et al. (1995) ArticleTitleEstablishment and molecular characterization of a novel leukemic cell line with Philadelphia chromosome expressing p230 Bcr-Abl fusion protein Cancer Res 55 3192–3196 Occurrence Handle7606740 Occurrence Handle1:CAS:528:DyaK2MXmvVyitb8%3D

    PubMed  CAS  Google Scholar 

  11. JV Melo (1996) ArticleTitleThe diversity of Bcr-Abl fusion proteins and their relationship to leukemia phenotype Blood 88 2375–2384 Occurrence Handle8839828 Occurrence Handle1:CAS:528:DyaK28XmtFSjtLY%3D

    PubMed  CAS  Google Scholar 

  12. RW Bolin WA Robinson J Sutherland RF Hamman (1982) ArticleTitleBusulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia Cancer 50 1683–1686 Occurrence Handle6956430 Occurrence Handle1:STN:280:DyaL3s%2FgtFKhtw%3D%3D Occurrence Handle10.1002/1097-0142(19821101)50:9<1683::AID-CNCR2820500904>3.0.CO;2-X

    Article  PubMed  CAS  Google Scholar 

  13. J Goldman (2003) ArticleTitleManagement of chronic myeloid leukemia Semin Hematol 40 1–103 Occurrence Handle12563606 Occurrence Handle10.1016/S0037-1963(03)70037-7

    Article  PubMed  Google Scholar 

  14. HM Kantarjian TL Smith S O'Brien et al. (1995) ArticleTitleProlonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service Ann Intern Med 122 254–261 Occurrence Handle7825760 Occurrence Handle1:STN:280:DyaK2M7is1ejtw%3D%3D

    PubMed  CAS  Google Scholar 

  15. JM Goldman (1992) ArticleTitleBone marrow transplantation for chronic myeloid leukaemia Leukemia 6 IssueIDSuppl 2 22–23 Occurrence Handle1578936

    PubMed  Google Scholar 

  16. S Kimura T Maekawa (2006) Stem cell transplantation for Ph+ leukemias in the imatinib and post-imatinib eras DF Davidson (Eds) Bone marrow transplantation: new research (review) Nova Science Publishers New York 1–38

    Google Scholar 

  17. N Heisterkamp G Jenster J ten Hoeve et al. (1990) ArticleTitleAcute leukaemia in bcr/abl transgenic mice Nature 344 251–253 Occurrence Handle2179728 Occurrence Handle1:STN:280:DyaK3c7ptVynsA%3D%3D Occurrence Handle10.1038/344251a0

    Article  PubMed  CAS  Google Scholar 

  18. GQ Daley RA Van Etten D Baltimore (1990) ArticleTitleInduction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome Science 247 824–830 Occurrence Handle2406902 Occurrence Handle1:CAS:528:DyaK3cXhsFaqs7c%3D Occurrence Handle10.1126/science.2406902

    Article  PubMed  CAS  Google Scholar 

  19. WS Pear JP Miller L Xu et al. (1998) ArticleTitleEfficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow Blood 92 3780–3792 Occurrence Handle9808572 Occurrence Handle1:CAS:528:DyaK1cXnsVKltrc%3D

    PubMed  CAS  Google Scholar 

  20. DS Krause RA Van Etten (2005) ArticleTitleTyrosine kinases as targets for cancer therapy N Engl J Med 353 172–187 Occurrence Handle16014887 Occurrence Handle1:CAS:528:DC%2BD2MXmtFClsbs%3D Occurrence Handle10.1056/NEJMra044389

    Article  PubMed  CAS  Google Scholar 

  21. T Skorski M Nieborowska-Skorska NC Nicolaides et al. (1994) ArticleTitleSuppression of Philadelphia1 leukemia cell growth in mice by Bcr-Abl antisense oligodeoxynucleotide Proc Natl Acad Sci USA 91 4504–4508 Occurrence Handle8183938 Occurrence Handle1:CAS:528:DyaK2cXkt1Knsbw%3D Occurrence Handle10.1073/pnas.91.10.4504

    Article  PubMed  CAS  Google Scholar 

  22. T Maekawa S Kimura K Hirakawa et al. (1995) ArticleTitleSequence specificity on the growth suppression and induction of apoptosis of chronic myeloid leukemia cells by Bcr-Abl antisense oligonucleotide phosphorothioates Int J Cancer 62 63–69 Occurrence Handle7601569 Occurrence Handle1:CAS:528:DyaK2MXnt1Cjtb8%3D Occurrence Handle10.1002/ijc.2910620113

    Article  PubMed  CAS  Google Scholar 

  23. RA Van Etten (2003) ArticleTitlec-Abl regulation: a tail of two lipids Curr Biol 13 R608–R610 Occurrence Handle12906815 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Kitr4%3D Occurrence Handle10.1016/S0960-9822(03)00528-1

    Article  PubMed  CAS  Google Scholar 

  24. KM Smith R Yacobi RA Van Etten (2003) ArticleTitleAutoinhibition of Bcr-Abl through its SH3 domain Mol Cell 12 27–37 Occurrence Handle12887890 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Cqtbk%3D Occurrence Handle10.1016/S1097-2765(03)00274-0

    Article  PubMed  CAS  Google Scholar 

  25. E Buchdunger J Zimmermann H Mett et al. (1996) ArticleTitleInhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 56 100–104 Occurrence Handle8548747 Occurrence Handle1:CAS:528:DyaK28Xit1Chsg%3D%3D

    PubMed  CAS  Google Scholar 

  26. T Schindler W Bornmann P Pellicena et al. (2000) ArticleTitleStructural mechanism for STI-571 inhibition of abelson tyrosine kinase Science 289 1938–1942 Occurrence Handle10988075 Occurrence Handle1:CAS:528:DC%2BD3cXms1altLc%3D Occurrence Handle10.1126/science.289.5486.1938

    Article  PubMed  CAS  Google Scholar 

  27. C Gambacorti-Passerini CP Le L Mologni et al. (1997) ArticleTitleInhibition of the Abl kinase activity blocks the proliferation of Bcr-Abl+ leukemic cells and induces apoptosis Blood Cells Mol Dis 23 380–394 Occurrence Handle9446752 Occurrence Handle1:CAS:528:DyaK1cXhsF2gtro%3D Occurrence Handle10.1006/bcmd.1997.0155

    Article  PubMed  CAS  Google Scholar 

  28. MW Deininger JM Goldman N Lydon et al. (1997) ArticleTitleThe tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of Bcr-Abl-positive cells Blood 90 3691–3698 Occurrence Handle9345054 Occurrence Handle1:CAS:528:DyaK2sXntVSqu7Y%3D

    PubMed  CAS  Google Scholar 

  29. BJ Druker S Tamura E Buchdunger et al. (1996) ArticleTitleEffects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells Nat Med 2 561–566 Occurrence Handle8616716 Occurrence Handle1:CAS:528:DyaK28Xislyhs70%3D Occurrence Handle10.1038/nm0596-561

    Article  PubMed  CAS  Google Scholar 

  30. BJ Druker (2001) ArticleTitleSignal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia Semin Hematol 38 3 IssueIDSuppl 8 9–14 Occurrence Handle10.1016/S0037-1963(01)90112-X

    Article  Google Scholar 

  31. BJ Druker M Talpaz DJ Resta et al. (2001) ArticleTitleEfficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia N Engl J Med 344 1031–1037 Occurrence Handle11287972 Occurrence Handle1:CAS:528:DC%2BD3MXivFGnu70%3D Occurrence Handle10.1056/NEJM200104053441401

    Article  PubMed  CAS  Google Scholar 

  32. K Arnold (2001) ArticleTitleAfter 30 years of laboratory work, a quick approval for STI571 J Natl Cancer Inst 93 IssueID13 972 Occurrence Handle11438558 Occurrence Handle1:STN:280:DC%2BD3MzosVOqsA%3D%3D Occurrence Handle10.1093/jnci/93.13.972

    Article  PubMed  CAS  Google Scholar 

  33. SG O'Brien F Guilhot RA Larson et al. (2003) ArticleTitleImatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med 348 994–1004 Occurrence Handle12637609 Occurrence Handle10.1056/NEJMoa022457

    Article  PubMed  Google Scholar 

  34. JM Goldman JV Melo (2003) ArticleTitleChronic myeloid leukemia – advances in biology and new approaches to treatment N Engl J Med 349 1451–1464 Occurrence Handle14534339 Occurrence Handle1:CAS:528:DC%2BD3sXotVGgsLc%3D Occurrence Handle10.1056/NEJMra020777

    Article  PubMed  CAS  Google Scholar 

  35. BJ Druker F Guilhot SG O'Brien et al. (2006) ArticleTitleFive-year follow-up of patients receiving imatinib for chronic myeloid leukemia N Engl J Med 355 2408–2417 Occurrence Handle17151364 Occurrence Handle1:CAS:528:DC%2BD28Xht12ntrzM Occurrence Handle10.1056/NEJMoa062867

    Article  PubMed  CAS  Google Scholar 

  36. CL Sawyers A Hochhaus E Feldman et al. (2002) ArticleTitleImatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study Blood 99 3530–3539 Occurrence Handle11986204 Occurrence Handle1:CAS:528:DC%2BD38XjvVGns78%3D Occurrence Handle10.1182/blood.V99.10.3530

    Article  PubMed  CAS  Google Scholar 

  37. J Cools DJ DeAngelo J Gotlib et al. (2003) ArticleTitleA tyrosine kinase created by fusion of the PDGFA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome N Engl J Med 348 1201–1214 Occurrence Handle12660384 Occurrence Handle1:CAS:528:DC%2BD3sXisVCqtrY%3D Occurrence Handle10.1056/NEJMoa025217

    Article  PubMed  CAS  Google Scholar 

  38. A Pardanani RP Ketterling SR Brockman et al. (2003) ArticleTitleCHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy Blood 102 3093–3096 Occurrence Handle12842979 Occurrence Handle1:CAS:528:DC%2BD3sXoslektbo%3D Occurrence Handle10.1182/blood-2003-05-1627

    Article  PubMed  CAS  Google Scholar 

  39. TR Golub GF Barker M Lovett et al. (1994) ArticleTitleFusion of the PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation Cell 77 307–316 Occurrence Handle8168137 Occurrence Handle1:CAS:528:DyaK2cXksFCrtb0%3D Occurrence Handle10.1016/0092-8674(94)90322-0

    Article  PubMed  CAS  Google Scholar 

  40. M Baccarani G Saglio J Goldman et al. (2006) ArticleTitleEvolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemia net Blood 108 1809–1820 Occurrence Handle16709930 Occurrence Handle1:CAS:528:DC%2BD28Xpsl2isrc%3D Occurrence Handle10.1182/blood-2006-02-005686

    Article  PubMed  CAS  Google Scholar 

  41. A Hochhaus P La Rosee (2004) ArticleTitleImatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance Leukemia 18 1321–1331 Occurrence Handle15215876 Occurrence Handle1:CAS:528:DC%2BD2cXlvVehs7g%3D Occurrence Handle10.1038/sj.leu.2403426

    Article  PubMed  CAS  Google Scholar 

  42. ME Gorre M Mohammed K Ellwood et al. (2001) ArticleTitleClinical resistance to STI-571 cancer therapy caused by Bcr-Abl gene mutation or amplification Science 293 876–880 Occurrence Handle11423618 Occurrence Handle1:CAS:528:DC%2BD3MXlvVKrsbs%3D Occurrence Handle10.1126/science.1062538

    Article  PubMed  CAS  Google Scholar 

  43. T Hegedus L Orfi A Seprodi et al. (2002) ArticleTitleInteraction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1 Biochim Biophys Acta 1587 318–325 Occurrence Handle12084474 Occurrence Handle1:CAS:528:DC%2BD38XkslKju7g%3D

    PubMed  CAS  Google Scholar 

  44. H Burger H van Tol M Brok et al. (2005) ArticleTitleChronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of theABCG2 (BcrP) and ABCB1 (MDR1) drug transport pumps Cancer Biol Ther 4 747–752 Occurrence Handle15970668 Occurrence Handle1:CAS:528:DC%2BD28XjtlWktLc%3D Occurrence Handle10.4161/cbt.4.7.1826

    Article  PubMed  CAS  Google Scholar 

  45. M Kotaki T Motoji M Takanashi et al. (2003) ArticleTitleAnti-proliferative effect of the Abl tyrosine kinase inhibitor STI571 on the P-glycoprotein positive K562/ADM cell line Cancer Lett 199 61–68 Occurrence Handle12963124 Occurrence Handle1:CAS:528:DC%2BD3sXntVyls7o%3D Occurrence Handle10.1016/S0304-3835(03)00338-0

    Article  PubMed  CAS  Google Scholar 

  46. NJ Donato JY Wu J Stapley et al. (2003) ArticleTitleBCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571 Blood 101 690–698 Occurrence Handle12509383 Occurrence Handle1:CAS:528:DC%2BD3sXkvVajsw%3D%3D Occurrence Handle10.1182/blood.V101.2.690

    Article  PubMed  CAS  Google Scholar 

  47. Y Dai M Rahmani SJ Corey et al. (2004) ArticleTitleA Bcr-Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2 J Biol Chem 279 34227–34239 Occurrence Handle15175350 Occurrence Handle1:CAS:528:DC%2BD2cXmvFent7g%3D Occurrence Handle10.1074/jbc.M402290200

    Article  PubMed  CAS  Google Scholar 

  48. A Ptasznik Y Nakata A Kalota et al. (2004) ArticleTitleShort interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, Bcr-Abl1(+) leukemia cells Nat Med 10 1187–1189 Occurrence Handle15502840 Occurrence Handle1:CAS:528:DC%2BD2cXptVOgtro%3D Occurrence Handle10.1038/nm1127

    Article  PubMed  CAS  Google Scholar 

  49. C Gambacorti-Passerini R Barni P le Coutre et al. (2000) ArticleTitleRole 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 1641–1650 Occurrence Handle11036109 Occurrence Handle1:CAS:528:DC%2BD3cXnvV2mtb8%3D Occurrence Handle10.1093/jnci/92.20.1641

    Article  PubMed  CAS  Google Scholar 

  50. J Thomas L Wang RE Clark et al. (2004) ArticleTitleActive transport of imatinib into and out of cells: implications for drug resistance Blood 104 3739–3745 Occurrence Handle15315971 Occurrence Handle1:CAS:528:DC%2BD2cXhtVGltb3M Occurrence Handle10.1182/blood-2003-12-4276

    Article  PubMed  CAS  Google Scholar 

  51. WK Hofmann LC Jones NA Lemp et al. (2002) ArticleTitlePh(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique Bcr-Abl gene mutation Blood 99 1860–1862 Occurrence Handle11861307 Occurrence Handle10.1182/blood.V99.5.1860

    Article  PubMed  Google Scholar 

  52. S Branford Z Rudzki S Walsh et al. (2003) ArticleTitleDetection of Bcr-Abl mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in theATP phosphate-binding loop (P-loop) are associated with a poor prognosis Blood 102 276–283 Occurrence Handle12623848 Occurrence Handle1:CAS:528:DC%2BD3sXltFemu7k%3D Occurrence Handle10.1182/blood-2002-09-2896

    Article  PubMed  CAS  Google Scholar 

  53. V Nardi M Azam GQ Daley (2004) ArticleTitleMechanisms and implications of imatinib resistance mutations in Bcr-Abl Curr Opin Hematol 11 35–43 Occurrence Handle14676625 Occurrence Handle1:CAS:528:DC%2BD2cXitVyrtbk%3D Occurrence Handle10.1097/00062752-200401000-00006

    Article  PubMed  CAS  Google Scholar 

  54. M Deininger E Buchdunger BJ Druker (2005) ArticleTitleThe development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood 105 2640–2653 Occurrence Handle15618470 Occurrence Handle1:CAS:528:DC%2BD2MXivFGmsb0%3D Occurrence Handle10.1182/blood-2004-08-3097

    Article  PubMed  CAS  Google Scholar 

  55. S Soverini G Martinelli G Rosti et al. (2005) ArticleTitleAbl mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia J Clin Oncol 23 4100–4109 Occurrence Handle15867198 Occurrence Handle1:CAS:528:DC%2BD2MXmt1emu7Y%3D Occurrence Handle10.1200/JCO.2005.05.531

    Article  PubMed  CAS  Google Scholar 

  56. NP Shah JM Nicoll B Nagar et al. (2002) ArticleTitleMultiple 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 2 117–125 Occurrence Handle12204532 Occurrence Handle1:CAS:528:DC%2BD38XmslSks7c%3D Occurrence Handle10.1016/S1535-6108(02)00096-X

    Article  PubMed  CAS  Google Scholar 

  57. A Hochhaus (2003) ArticleTitleCytogenetic and molecular mechanisms of resistance to imatinib Semin Hematol 40 IssueIDSuppl 2 69–79 Occurrence Handle12783379 Occurrence Handle1:CAS:528:DC%2BD3sXlt1yrur4%3D

    PubMed  CAS  Google Scholar 

  58. HM Kantarjian M Talpaz F Giles et al. (2006) ArticleTitleNew insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance Ann Intern Med 145 913–923 Occurrence Handle17179059

    PubMed  Google Scholar 

  59. T Schindler W Bornmann P Pellicena et al. (2000) ArticleTitleStructural mechanism for STI-571 inhibition of abelson tyrosine kinase Science 289 1938–1942 Occurrence Handle10988075 Occurrence Handle1:CAS:528:DC%2BD3cXms1altLc%3D Occurrence Handle10.1126/science.289.5486.1938

    Article  PubMed  CAS  Google Scholar 

  60. CB Gambacorti-Passerini RH Gunby R Piazza et al. (2003) ArticleTitleMolecular mechanisms of resistance to imatinib in Philadelphia chromosome-positive leukaemias Lancet Oncol 4 75–85 Occurrence Handle12573349 Occurrence Handle10.1016/S1470-2045(03)00979-3

    Article  PubMed  Google Scholar 

  61. S Soverini G Martinelli G Rosti et al. (2005) ArticleTitleAbl mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia J Clin Oncol 23 4100–4109 Occurrence Handle15867198 Occurrence Handle1:CAS:528:DC%2BD2MXmt1emu7Y%3D Occurrence Handle10.1200/JCO.2005.05.531

    Article  PubMed  CAS  Google Scholar 

  62. S Soverini G Martinelli M Amabile et al. (2004) ArticleTitleDenaturing-HPLC-based assay for detection of Abl mutations in chronic myeloid leukemia patients resistant to Imatinib Clin Chem 50 1205–1213 Occurrence Handle15107311 Occurrence Handle1:CAS:528:DC%2BD2cXlsFWgur0%3D Occurrence Handle10.1373/clinchem.2004.031112

    Article  PubMed  CAS  Google Scholar 

  63. J Cortes F Giles S O'Brien et al. (2003) ArticleTitleResult of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha Blood 102 83–86 Occurrence Handle12637317 Occurrence Handle1:CAS:528:DC%2BD3sXltFemtb8%3D Occurrence Handle10.1182/blood-2003-01-0025

    Article  PubMed  CAS  Google Scholar 

  64. S O'Brien F Giles M Talpaz et al. (2003) ArticleTitleResults of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase Cancer 98 888–893 Occurrence Handle12942553 Occurrence Handle10.1002/cncr.11620 Occurrence Handle1:CAS:528:DC%2BD3sXns1Sjsr8%3D

    Article  PubMed  CAS  Google Scholar 

  65. J Kuroda S Kimura Y Kobayashi et al. (2003) ArticleTitleThe third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate Blood 102 2229–2235 Occurrence Handle12763930 Occurrence Handle1:CAS:528:DC%2BD3sXntlKrsL0%3D Occurrence Handle10.1182/blood-2003-01-0305

    Article  PubMed  CAS  Google Scholar 

  66. H Kantarjian M Talpaz S O'Brien et al. (2004) ArticleTitleHigh-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia Blood 103 2873–2878 Occurrence Handle15070658 Occurrence Handle1:CAS:528:DC%2BD2cXjsVahuro%3D Occurrence Handle10.1182/blood-2003-11-3800

    Article  PubMed  CAS  Google Scholar 

  67. C Abram S Courtneidge (2000) ArticleTitleSrc family tyrosine kinases and growth factor signaling Exp Cell Res 254 1–13 Occurrence Handle10623460 Occurrence Handle1:CAS:528:DC%2BD3cXht1ChsQ%3D%3D Occurrence Handle10.1006/excr.1999.4732

    Article  PubMed  CAS  Google Scholar 

  68. S Danhauser-Riedl Druker BJ WarmuthM et al. (1996) ArticleTitleActivation of Src kinases p53/56lyn and p59hck by p210Bcr-Abl in myeloid cells Cancer Res 56 3589–3596 Occurrence Handle8758931 Occurrence Handle1:CAS:528:DyaK28Xks1eltr4%3D

    PubMed  CAS  Google Scholar 

  69. M Stanglmaier M Warmuth I Kleinlein et al. (2003) ArticleTitleThe interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains Leukemia 17 283–289 Occurrence Handle12592324 Occurrence Handle1:CAS:528:DC%2BD3sXht1Glt7g%3D Occurrence Handle10.1038/sj.leu.2402778

    Article  PubMed  CAS  Google Scholar 

  70. N Donato J Wu J Stapley et al. (2004) ArticleTitleImatinib mesylate resistance through Bcr-Abl independence in chronic myelogenous leukemia Cancer Res 64 672–677 Occurrence Handle14744784 Occurrence Handle1:CAS:528:DC%2BD2cXmsVagsw%3D%3D Occurrence Handle10.1158/0008-5472.CAN-03-1484

    Article  PubMed  CAS  Google Scholar 

  71. W Hofmann S de Vos D Elashoff et al. (2002) ArticleTitleRelation between resistance of Philadelphia-chromosome positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study Lancet 359 481–486 Occurrence Handle11853794 Occurrence Handle1:CAS:528:DC%2BD38Xhtlektrc%3D Occurrence Handle10.1016/S0140-6736(02)07678-X

    Article  PubMed  CAS  Google Scholar 

  72. B Nagar WG Bornmann P Pellicena et al. (2002) ArticleTitleCrystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571) Cancer Res 62 4236–4243 Occurrence Handle12154025 Occurrence Handle1:CAS:528:DC%2BD38XlvFeltLY%3D

    PubMed  CAS  Google Scholar 

  73. A Klejman SJ Schreiner M Nieborowska-Skorska et al. (2002) ArticleTitleThe Src family kinase Hck couples Bcr-Abl to STAT5 activation in myeloid leukemia cells EMBO J 21 5766–5774 Occurrence Handle12411494 Occurrence Handle1:CAS:528:DC%2BD38XosVSrt78%3D Occurrence Handle10.1093/emboj/cdf562

    Article  PubMed  CAS  Google Scholar 

  74. Y Hu Y Liu S Pelletier et al. (2004) ArticleTitleRequirement of Src kinases Lyn, Hck, and Fgr for Bcr-Abl1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia Nat Genet 36 453–461 Occurrence Handle15098032 Occurrence Handle1:CAS:528:DC%2BD2cXjsFSnt74%3D Occurrence Handle10.1038/ng1343

    Article  PubMed  CAS  Google Scholar 

  75. A Ptasznik Y Nakata A Kalota et al. (2004) ArticleTitleShort interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug resistant, Bcr-Abl1(+) leukemia cells Nat Med 10 1187–1189 Occurrence Handle15502840 Occurrence Handle1:CAS:528:DC%2BD2cXptVOgtro%3D Occurrence Handle10.1038/nm1127

    Article  PubMed  CAS  Google Scholar 

  76. M Talpaz NP Shah H Kantarjian et al. (2006) ArticleTitleDasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias N Engl J Med 354 2531–2541 Occurrence Handle16775234 Occurrence Handle1:CAS:528:DC%2BD28Xlslyisb0%3D Occurrence Handle10.1056/NEJMoa055229

    Article  PubMed  CAS  Google Scholar 

  77. NP Shah C Tran FY Lee et al. (2004) ArticleTitleOverriding imatinib resistance with a novel ABL kinase inhibitor Science 305 399–401 Occurrence Handle15256671 Occurrence Handle1:CAS:528:DC%2BD2cXls1egtrY%3D Occurrence Handle10.1126/science.1099480

    Article  PubMed  CAS  Google Scholar 

  78. T O'Hare DK Walters EP Stoffregen et al. (2005) ArticleTitleIn vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants Cancer Res 65 4500–4555 Occurrence Handle15930265 Occurrence Handle10.1158/0008-5472.CAN-05-0259

    Article  PubMed  Google Scholar 

  79. E Weisberg PW Manley W Breitenstein et al. (2005) ArticleTitleCharacterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 7 129–141 Occurrence Handle15710326 Occurrence Handle1:CAS:528:DC%2BD2MXitFygu7o%3D Occurrence Handle10.1016/j.ccr.2005.01.007

    Article  PubMed  CAS  Google Scholar 

  80. C Gambacorti-Passerini M Gasser S Ahmed et al. (2005) ArticleTitleAbl inhibitor BMS354825 binding mode in Abelson kinase revealed by molecular docking studies Leukemia 19 1267–1269 Occurrence Handle15858616 Occurrence Handle1:CAS:528:DC%2BD2MXmvVOjurc%3D Occurrence Handle10.1038/sj.leu.2403775

    Article  PubMed  CAS  Google Scholar 

  81. SW Cowan-Jacob V Guez G Fendrich et al. (2004) ArticleTitleImatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment Mini Rev Med Chem 4 285–299 Occurrence Handle15032675 Occurrence Handle1:CAS:528:DC%2BD2cXisVKhur8%3D Occurrence Handle10.2174/1389557043487321

    Article  PubMed  CAS  Google Scholar 

  82. LJ Lombardo FY Lee P Chen et al. (2004) ArticleTitleDiscovery 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 6658–6661 Occurrence Handle15615512 Occurrence Handle1:CAS:528:DC%2BD2cXhtVKrsrnI Occurrence Handle10.1021/jm049486a

    Article  PubMed  CAS  Google Scholar 

  83. JS Tokarski JA Newitt CY Chang et al. (2006) ArticleTitleThe structure of Dasatinib (BMS-354825) bound to activated Abl kinase domain elucidates its inhibitory activity against imatinib-resistant Abl mutants Cancer Res 66 5790–5797 Occurrence Handle16740718 Occurrence Handle1:CAS:528:DC%2BD28XltFyjtbw%3D Occurrence Handle10.1158/0008-5472.CAN-05-4187

    Article  PubMed  CAS  Google Scholar 

  84. MR Burgess BJ Skaggs NP Shah et al. (2005) ArticleTitleComparative analysis of two clinically active Bcr-Abl kinase inhibitors reveals the role of conformation-specific binding in resistance Proc Natl Acad Sci USA 102 3395–3400 Occurrence Handle15705718 Occurrence Handle1:CAS:528:DC%2BD2MXitl2lurk%3D Occurrence Handle10.1073/pnas.0409770102

    Article  PubMed  CAS  Google Scholar 

  85. S Soverini G Martinelli S Colarossi et al. (2007) ArticleTitleSecond-line treatment with dasatinib in patients resistant to imatinib can select novel inhibitor-specific BCR-ABL mutants in Ph+ ALL Lancet Oncol 8 273–274 Occurrence Handle17329198 Occurrence Handle10.1016/S1470-2045(07)70078-5

    Article  PubMed  Google Scholar 

  86. HM Kantarjian F Giles A Quintas-Cardama et al. (2007) ArticleTitleImportant therapeutic targets in chronic myelogenous leukemia Clin Cancer Res 13 1089–1097 Occurrence Handle17317816 Occurrence Handle1:CAS:528:DC%2BD2sXhvF2hsL4%3D Occurrence Handle10.1158/1078-0432.CCR-06-2147

    Article  PubMed  CAS  Google Scholar 

  87. A Hochhaus H Kantarjian M Baccarini et al. (2006) ArticleTitleDasatinib efficacy and safety in patients with chronic phase CML resistant or intolerant to imatinib: results of the CA180013 “START-C” phase II study (abstract 6508) J Clin Oncol 24 339s

    Google Scholar 

  88. F Guilhot J Apperley DW Kim et al. (2007) ArticleTitleDasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase Blood 109 4143–4150 Occurrence Handle17264298 Occurrence Handle1:CAS:528:DC%2BD2sXls1anurc%3D Occurrence Handle10.1182/blood-2006-09-046839

    Article  PubMed  CAS  Google Scholar 

  89. J Cortes D Kim P Rosti et al. (2006) ArticleTitleDasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): results of the CA180006 “START-B” study (abstract 6529) J Clin Oncol 24 344s Occurrence Handle10.1200/JCO.2006.07.0151

    Article  Google Scholar 

  90. S Coutre G Martinelli H Dombret et al. (2006) ArticleTitleDasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): the CA180015 ‘START-L’ study (abstract 6528) J Clin Oncol 24 344s

    Google Scholar 

  91. N Shah P Rousselot R Pasquini et al. (2006) ArticleTitleDasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial (abstract 6507) J Clin Oncol 24 338s Occurrence Handle10.1200/JCO.2006.08.0887 Occurrence Handle1:CAS:528:DC%2BD28XhtlemurbM

    Article  CAS  Google Scholar 

  92. A Quintas-Cardama H Kantarjian D Jones et al. (2007) ArticleTitleDasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure Blood 109 497–499 Occurrence Handle16990591 Occurrence Handle1:CAS:528:DC%2BD2sXivVykurY%3D Occurrence Handle10.1182/blood-2006-07-035493

    Article  PubMed  CAS  Google Scholar 

  93. HA Bradeen CA Eide T O'Hare et al. (2006) ArticleTitleComparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations Blood 108 2332–2338 Occurrence Handle16772610 Occurrence Handle1:CAS:528:DC%2BD28XhtVCgur%2FJ Occurrence Handle10.1182/blood-2006-02-004580

    Article  PubMed  CAS  Google Scholar 

  94. E Weisberg L Catley RD Wright et al. (2007) ArticleTitleBeneficial effects of combining nilotinib and imatinib in preclinical models of Bcr-Abl+ leukemias Blood 109 2112–2120 Occurrence Handle17068153 Occurrence Handle1:CAS:528:DC%2BD2sXjtFequrc%3D Occurrence Handle10.1182/blood-2006-06-026377

    Article  PubMed  CAS  Google Scholar 

  95. M Azam V Nardi WC Shakespeare et al. (2006) ArticleTitleActivity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance Proc Natl Acad Sci U S A 103 9244–9249 Occurrence Handle16754879 Occurrence Handle1:CAS:528:DC%2BD28XmsVWjtrc%3D Occurrence Handle10.1073/pnas.0600001103

    Article  PubMed  CAS  Google Scholar 

  96. T O'Hare R Pollock EP Stoffregen et al. (2004) ArticleTitleInhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML Blood 104 2532–2539 Occurrence Handle15256422 Occurrence Handle10.1182/blood-2004-05-1851 Occurrence Handle1:CAS:528:DC%2BD2cXovVegtbs%3D

    Article  PubMed  CAS  Google Scholar 

  97. JM Golas K Arndt C Etienne et al. (2003) ArticleTitleSKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice Cancer Res 63 375–381 Occurrence Handle12543790 Occurrence Handle1:CAS:528:DC%2BD3sXnt1Krsg%3D%3D

    PubMed  CAS  Google Scholar 

  98. http://www.clinicaltrials.gov/ct/show/NCT00261846?order=2. Accessed 10 May 2007

  99. http://www.clinicaltrials.gov/ct/show/NCT00195260?order=1. Accessed 11 Jul 2007

  100. JM Golas J Lucas C Etienne et al. (2005) ArticleTitleSKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models Cancer Res 65 5358–5364 Occurrence Handle15958584 Occurrence Handle1:CAS:528:DC%2BD2MXltFelsrk%3D Occurrence Handle10.1158/0008-5472.CAN-04-2484

    Article  PubMed  CAS  Google Scholar 

  101. M Sattler MG Mohi YB Pride et al. (2002) ArticleTitleCritical role for Gab2 in transformation by Bcr-Abl Cancer Cell 1 479–492 Occurrence Handle12124177 Occurrence Handle1:CAS:528:DC%2BD38XltVKjsbo%3D Occurrence Handle10.1016/S1535-6108(02)00074-0

    Article  PubMed  CAS  Google Scholar 

  102. E Weisberg PW Manley W Breitenstein et al. (2005) ArticleTitleCharacterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 7 129–141 Occurrence Handle15710326 Occurrence Handle1:CAS:528:DC%2BD2MXitFygu7o%3D Occurrence Handle10.1016/j.ccr.2005.01.007

    Article  PubMed  CAS  Google Scholar 

  103. T O'Hare DK Walters EP Stoffregen et al. (2005) ArticleTitleIn vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants Cancer Res 65 4500–4555 Occurrence Handle15930265 Occurrence Handle10.1158/0008-5472.CAN-05-0259

    Article  PubMed  Google Scholar 

  104. M Golemovic S Verstovsek F Giles et al. (2005) ArticleTitleAMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia Clin Cancer Res 11 4941–4947 Occurrence Handle16000593 Occurrence Handle1:CAS:528:DC%2BD2MXlvVGgsbY%3D Occurrence Handle10.1158/1078-0432.CCR-04-2601

    Article  PubMed  CAS  Google Scholar 

  105. H Kantarjian F Giles L Wunderle et al. (2006) ArticleTitleNilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL N Engl J Med 354 2542–2551 Occurrence Handle16775235 Occurrence Handle10.1056/NEJMoa055104

    Article  PubMed  Google Scholar 

  106. E Jabbour F Giles J Cortes et al. (2006) ArticleTitlePreliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP) J Clin Oncol 24 6591s

    Google Scholar 

  107. S Kimura H Naito H Segawa et al. (2005) ArticleTitleNS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia Blood 106 3948–3954 Occurrence Handle16105974 Occurrence Handle1:CAS:528:DC%2BD2MXht12ktrzL Occurrence Handle10.1182/blood-2005-06-2209

    Article  PubMed  CAS  Google Scholar 

  108. T Asaki Y Sugiyama T Hamamoto et al. (2006) ArticleTitleDesign and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors Bioorg Med Chem Lett 16 1421–1425 Occurrence Handle16332440 Occurrence Handle1:CAS:528:DC%2BD28Xosl2nsw%3D%3D Occurrence Handle10.1016/j.bmcl.2005.11.042

    Article  PubMed  CAS  Google Scholar 

  109. H Naito S Kimura Y Nakaya et al. (2006) ArticleTitleIn vivo inhibitory effect of NS-187, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor, on the proliferation of leukemic cells harbouring Abl kinase domain mutations Leuk Res 30 1443–1446 Occurrence Handle16546254 Occurrence Handle1:CAS:528:DC%2BD28Xptlyku70%3D Occurrence Handle10.1016/j.leukres.2006.01.006

    Article  PubMed  CAS  Google Scholar 

  110. A Yokota S Kimura S Masuda et al. (2007) ArticleTitleINNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity Blood 109 306–314 Occurrence Handle16954504 Occurrence Handle1:CAS:528:DC%2BD2sXivVyru7w%3D Occurrence Handle10.1182/blood-2006-03-013250

    Article  PubMed  CAS  Google Scholar 

  111. AR Craig HM Kantarjian JE Cortes et al. (2007) ArticleTitleA phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib (abstract 7046) J Clin Oncol 25 18s

    Google Scholar 

  112. K Gumireddy SJ Baker SC Cosenza et al. (2005) ArticleTitleA non-ATP-competitive inhibitor of Bcr-Abl overrides imatinib resistance Proc Natl Acad Sci U S A 102 1992–1997 Occurrence Handle15677719 Occurrence Handle1:CAS:528:DC%2BD2MXhvFGrurk%3D Occurrence Handle10.1073/pnas.0408283102

    Article  PubMed  CAS  Google Scholar 

  113. R Giet C Prigent (1999) ArticleTitleAurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases J Cell Sci 112 3591–3601 Occurrence Handle10523496 Occurrence Handle1:CAS:528:DyaK1MXns1OlsLo%3D

    PubMed  CAS  Google Scholar 

  114. EA Harrington D Bebbington J Moore et al. (2004) ArticleTitleVX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo Nat Med 10 262–267 Occurrence Handle14981513 Occurrence Handle1:CAS:528:DC%2BD2cXhs1Wnur4%3D Occurrence Handle10.1038/nm1003

    Article  PubMed  CAS  Google Scholar 

  115. MA Young NP Shah LH Chao et al. (2006) ArticleTitleStructure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680 Cancer Res 66 1007–1014 Occurrence Handle16424036 Occurrence Handle1:CAS:528:DC%2BD28XlsFOhtw%3D%3D Occurrence Handle10.1158/0008-5472.CAN-05-2788

    Article  PubMed  CAS  Google Scholar 

  116. FJ Giles J Cortes D Jones et al. (2007) ArticleTitleMK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation Blood 109 500–502 Occurrence Handle16990603 Occurrence Handle1:CAS:528:DC%2BD2sXivVykurc%3D Occurrence Handle10.1182/blood-2006-05-025049

    Article  PubMed  CAS  Google Scholar 

  117. http://www.clinicaltrials.gov/ct/show/NCT00405054?order=1. Accessed 1 Aug 2007

  118. TA Carter LM Wodicka NP Shah et al. (2005) ArticleTitleInhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases Proc Natl Acad Sci USA 102 11011–11016 Occurrence Handle16046538 Occurrence Handle1:CAS:528:DC%2BD2MXnvVWjurg%3D Occurrence Handle10.1073/pnas.0504952102

    Article  PubMed  CAS  Google Scholar 

  119. T O'Hare BJ Druker (2005) ArticleTitleBIRB-796 is not an effective ABL(T315I) inhibitor Nat Biotechnol 23 1209–1210 Occurrence Handle16211050 Occurrence Handle10.1038/nbt1005-1209 Occurrence Handle1:CAS:528:DC%2BD2MXhtVOhu7rM

    Article  PubMed  CAS  Google Scholar 

  120. Burley SK (2005) Application of FAST™ fragment-based lead discovery and structure-guided design to discovery of small molecule inhibitors of BCR-ABL tyrosine kinase active against T315I imanitib-resistant mutant (abstract 698[) Blood 106:11 (Suppl) 206a

  121. DJ Barnes JV Melo (2006) ArticleTitlePrimitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia Cell Cycle 5 2862–2866 Occurrence Handle17172863 Occurrence Handle1:CAS:528:DC%2BD2sXksVOit7w%3D

    PubMed  CAS  Google Scholar 

  122. HG Jorgensen TL Holyoake (2001) ArticleTitleA comparison of normal and leukemic stem cell biology in chronic myeloid leukemia Hematol Oncol 19 89–106 Occurrence Handle11574931 Occurrence Handle1:STN:280:DC%2BD3MrivVarsA%3D%3D Occurrence Handle10.1002/hon.667

    Article  PubMed  CAS  Google Scholar 

  123. M Dean T Fojo S Bates (2005) ArticleTitleTumour stem cells and drug resistance Nat Rev Cancer 5 275–284 Occurrence Handle15803154 Occurrence Handle1:CAS:528:DC%2BD2MXivVarsL4%3D Occurrence Handle10.1038/nrc1590

    Article  PubMed  CAS  Google Scholar 

  124. T Holyoake X Jiang C Eaves et al. (1999) ArticleTitleIsolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia Blood 94 2056–2064 Occurrence Handle10477735 Occurrence Handle1:CAS:528:DyaK1MXlvFCmsrg%3D

    PubMed  CAS  Google Scholar 

  125. T Maekawa D Metcalf (1991) Suppression of clonogenicity of human leukemic cells by recombinant hemopoietic factors T Miyazaki F Takaku H Uchino (Eds) Myelodysplastic syndrome and cytokines Elsevier Amsterdam 101–110

    Google Scholar 

  126. SM Graham HG Jorgensen E Allan et al. (2002) ArticleTitlePrimitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro Blood 99 319–325 Occurrence Handle11756187 Occurrence Handle1:CAS:528:DC%2BD38XivF2gug%3D%3D Occurrence Handle10.1182/blood.V99.1.319

    Article  PubMed  CAS  Google Scholar 

  127. MS Holtz ML Slovak F Zhang et al. (2002) ArticleTitleImatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation Blood 99 3792–3800 Occurrence Handle11986238 Occurrence Handle1:CAS:528:DC%2BD38XjvVGntLs%3D Occurrence Handle10.1182/blood.V99.10.3792

    Article  PubMed  CAS  Google Scholar 

  128. R Bhatia M Holtz N Niu et al. (2003) ArticleTitlePersistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment Blood 101 4701–4707 Occurrence Handle12576334 Occurrence Handle1:CAS:528:DC%2BD3sXkslequ7o%3D Occurrence Handle10.1182/blood-2002-09-2780

    Article  PubMed  CAS  Google Scholar 

  129. M Copland A Hamilton LJ Elrick et al. (2006) ArticleTitleDasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction Blood 107 4532–4539 Occurrence Handle16469872 Occurrence Handle1:CAS:528:DC%2BD28Xlt1CgtrY%3D Occurrence Handle10.1182/blood-2005-07-2947

    Article  PubMed  CAS  Google Scholar 

  130. HG Jorgensen EK Allan NE Jordanides et al. (2007) ArticleTitleNilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells Blood 109 4016–4019 Occurrence Handle17213283 Occurrence Handle1:CAS:528:DC%2BD2sXkvFCiurc%3D Occurrence Handle10.1182/blood-2006-11-057521

    Article  PubMed  CAS  Google Scholar 

  131. F Michor TP Hughes Y Iwasa et al. (2005) ArticleTitleDynamics of chronic myeloid leukaemia Nature 435 1267–1270 Occurrence Handle15988530 Occurrence Handle1:CAS:528:DC%2BD2MXls1Ontbo%3D Occurrence Handle10.1038/nature03669

    Article  PubMed  CAS  Google Scholar 

  132. NL Komarova D Wodarz (2005) ArticleTitleDrug resistance in cancer: principles of emergence and prevention Proc Natl Acad Sci USA 102 9714–9719 Occurrence Handle15980154 Occurrence Handle1:CAS:528:DC%2BD2MXmsVaktbY%3D Occurrence Handle10.1073/pnas.0501870102

    Article  PubMed  CAS  Google Scholar 

  133. T O'Hare DK Walters EP Stoffregen et al. (2005) ArticleTitleCombined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib Clin Cancer Res 11 IssueID19 Pt 1 6987–6993 Occurrence Handle16203792 Occurrence Handle10.1158/1078-0432.CCR-05-0622

    Article  PubMed  Google Scholar 

  134. DL White VA Saunders SR Quinn et al. (2007) ArticleTitleImatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs Blood 109 3609–3610 Occurrence Handle17409347 Occurrence Handle1:CAS:528:DC%2BD2sXksFWhsLY%3D Occurrence Handle10.1182/blood-2006-11-058032

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507, Japan

    Taira Maekawa, Eishi Ashihara & Shinya Kimura

Authors
  1. Taira Maekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eishi Ashihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shinya Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Taira Maekawa.

About this article

Cite this article

Maekawa, T., Ashihara, E. & Kimura, S. The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol 12, 327–340 (2007). https://doi.org/10.1007/s10147-007-0699-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-007-0699-1

Key words

Search

Navigation