Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Strategies to overcome resistance to targeted protein kinase inhibitors

Key Points

  • The success of kinase inhibitors, such as imatinib and gefitinib, has shown that the development of specific, targeted therapies for cancer is possible.

  • However, there have been many cases of drug resistance to imatinib observed in the clinic and this has consequences for the development of second-generation kinase inhibitors.

  • Current efforts are focused on characterizing the structural determinants of imatinib resistance observed in the clinic. These studies illustrate the importance of features such as the gatekeeper residue, the p-loop and the activation loop of protein kinases.

  • The design of more effective inhibitors based on this structural knowledge, combined with the development of multi-targeted kinase inhibitors that show improved efficacy, hold great promise for cancer therapy.

Abstract

Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR–ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr–Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Potential mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemia.
Figure 2: Mutational hotspots conferring imatinib resistance to Bcr–Abl.
Figure 3: Sequence alignments of the imatinib targets Abl, PDGFRα and Kit.
Figure 4: Chemical structures of the imatinib back-up drugs.
Figure 5: Relevance of the gatekeeper residue for inhibitor binding.
Figure 6: Chemical structures of the indolinone compounds.

References

  1. 1

    Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Kaelin, W. G. Jr. Gleevec: prototype or outlier? Sci. STKE 2004, PE12 (2004).

    Google Scholar 

  3. 3

    Cohen, P. Protein kinases — the major drug targets of the twenty-first century? Nature Rev. Drug Discov. 1, 309–315 (2002).

    CAS  Google Scholar 

  4. 4

    Dancey, J. & Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nature Rev. Drug Discov. 2, 296–313 (2003).

    CAS  Google Scholar 

  5. 5

    Gschwind, A., Fischer, O. M. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Rev. Cancer 4, 361–370 (2004).

    CAS  Google Scholar 

  6. 6

    Coates, A., Hu, Y., Bax, R. & Page C. The future challenges facing the development of new antimicrobial drugs. Nature Rev. Drug Discov. 1, 895–910 (2002).

    CAS  Google Scholar 

  7. 7

    Walsh, C. Molecular mechanisms that confer antibacterial drug resistance. Nature 406, 775–781 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    von Bubnoff, N., Peschel, C. & Duyster, J. Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia 17, 829–838 (2003).

    CAS  Google Scholar 

  9. 9

    Cowan-Jacob, S. W. et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev. Med. Chem. 4, 285–299 (2004).

    CAS  PubMed  Google Scholar 

  10. 10

    Hochhaus, A. & La Rosee, P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18, 1321–1331 (2004).

    CAS  Google Scholar 

  11. 11

    Nardi, V., Azam, M. & Daley, G. Q. Mechanisms and implications of imatinib resistance mutations in BCR–ABL. Curr. Opin. Hematol. 11, 35–43 (2004).

    CAS  Google Scholar 

  12. 12

    Ross, D. M. & Hughes, T. P. Cancer treatment with kinase inhibitors: what have we learnt from imatinib? Br. J. Cancer 90, 12–19 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002).

    CAS  Google Scholar 

  14. 14

    Faderl, S. et al. The biology of chronic myeloid leukemia. N. Engl. J. Med. 341, 164–172 (1999).

    CAS  Google Scholar 

  15. 15

    Sawyers, C. L. Chronic myeloid leukaemia. N. Engl. J. Med. 340, 1330–1340 (1999).

    CAS  Google Scholar 

  16. 16

    Daley, G. Q., van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the p210Bcr/Abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

    CAS  Google Scholar 

  17. 17

    Lugo, T. G. et al. Tyrosine kinase activity and transformation potency of Bcr–Abl oncogene products. Science 247, 1079–1082 (1990).

    CAS  Google Scholar 

  18. 18

    Druker, B. G. 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. 344, 1038–1042 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nature Med. 2, 561–566 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Ottmann, O. G. et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100, 1965–1971 (2002).

    CAS  PubMed  Google Scholar 

  21. 21

    Druker, B. J. Imatinib as a paradigm of targeted therapies. Adv. Cancer Res. 91, 1–30 (2004).

    CAS  Google Scholar 

  22. 22

    Hingorani, S. R. & Tuveson, D. A. Targeting oncogene dependence and resistance. Cancer Cell 3, 414–417 (2003).

    CAS  Google Scholar 

  23. 23

    Gambacorti-Passerini, C. et al. α1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin. Cancer Res. 9, 625–632 (2003).

    CAS  Google Scholar 

  24. 24

    Mahon, F. X. et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101, 2368–2373 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Thomas, J., Wang, L., Clark, R. E. & Pirmohamed, M. Active transport of imatinib into and out of cells: Implications for drug resistance. Blood 17 Aug 2004 (doi:10.1182/blood-2003-12-4276).

  26. 26

    Donato, N. J. et al. BCR–ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698 (2003).

    CAS  Google Scholar 

  27. 27

    Dai, Y., Rahmani, M., Corey, S. J., Dent, P. & Grant, S. 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, 34227–34239 (2004).

    CAS  Google Scholar 

  28. 28

    Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR–ABL gene mutation or amplification. Science 293, 876–880 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Branford, S. et al. 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, 3472–3475 (2002).

    CAS  PubMed  Google Scholar 

  31. 31

    Hofmann, W. K. et al. Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR–ABL gene mutation. Blood 99, 1860–1862 (2002).

    Google Scholar 

  32. 32

    Roumiantsev, S. et al. 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, 10700–10705 (2002).

    CAS  PubMed  Google Scholar 

  33. 33

    Shah, N. P. 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 2, 117–125 (2002). An excellent paper about the amino-acid substitutions in Bcr–Abl from relapsed CML patients and the potential mechanisms how these mutations confer imatinib resistance.

    CAS  Google Scholar 

  34. 34

    von Bubnoff, N., Schneller, F., Peschel, C. & Duyster, J. BCR–ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 359, 487–491 (2002).

    CAS  PubMed  Google Scholar 

  35. 35

    Corbin, A. S., La Rosee, P., Stoffregen, E. P., Druker, B. J. & Deininger, M. W. Several Bcr–Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 101, 4611–4614 (2003).

    CAS  Google Scholar 

  36. 36

    Schindler, T. et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938–1942 (2000). First report of the co-crystal structure of an imatinib analogue in complex with the tyrosine kinase Abl.

    CAS  PubMed  Google Scholar 

  37. 37

    Blencke, S. et al. Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors. Chem. Biol. 11, 691–791 (2004). This study provides an analysis of the 'gatekeeper' residue in several tyrosine kinases and shows the general relevance of this site for resistance formation against small-molecule inhibitors.

    CAS  Google Scholar 

  38. 38

    Nagar, B. 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. 62, 4236–4243 (2002).

    CAS  PubMed  Google Scholar 

  39. 39

    Branford, 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 102, 276–832 (2003). This study shows that the type of the imatinib resistance-inducing mutation in BCR–ABL predicts the clinical prognosis for relapsed CML patients.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Azam, M., Latek, R. R. & Daley, G. Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR–ABL. Cell 112, 831–843 (2003). This paper describes an interesting screening technique to identify potential mechanisms of resistance to targeted kinase inhibitors.

    CAS  Google Scholar 

  41. 41

    Apperley, J. F. 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. 347, 481–487 (2002).

    CAS  Google Scholar 

  42. 42

    Cools, 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. 348, 1201–1214 (2003). This study identifies a constitutively active PDGFRα variant as imatinib target in a haematologic disorder and further reports the emergence of imatinib resistance as a consequence of a mutation affecting the PDGFRα residue homologous to Thr315 in Abl.

    CAS  PubMed  Google Scholar 

  43. 43

    Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Tamborini, E. et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127, 294–299 (2004).

    CAS  Google Scholar 

  45. 45

    Wakai, T. et al. Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br. J. Cancer 90, 2059–2061 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ma, Y. 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 99, 1741–1744 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Wisniewski, D. et al. Characterization of potent inhibitors of the Bcr–Abl and the c-kit receptor tyrosine kinases. Cancer Res. 62, 4244–4255 (2002).

    CAS  Google Scholar 

  48. 48

    La Rosée, P., Corbin, A. S., Stoffregen, E. P., Deininger, M. W. & Druker, B. J. Activity of the Bcr–Abl kinase inhibitor PD180970 against clinically relevant Bcr–Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res. 62, 7149–7153 (2002). This is the first report demonstrating that many imatinib-restistant Bcr–Abl variants retain sensitivity to a structurally distinct kinase inhibitor.

    Google Scholar 

  49. 49

    Huron, D. R. 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. 9, 1267–1273 (2003).

    CAS  PubMed  Google Scholar 

  50. 50

    von Bubnoff, N. et al. Inhibition of wild-type and mutant Bcr–Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. Cancer Res. 63, 6395–6404 (2003).

    CAS  Google Scholar 

  51. 51

    Kantarjian, H. M. et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101, 473–475 (2003).

    CAS  Google Scholar 

  52. 52

    Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).

    CAS  PubMed  Google Scholar 

  53. 53

    O'Hare, T. et al. Inhibition of wild-type and mutant Bcr–Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: Implications for CML. Blood 104, 2532–2539 (2004).

    CAS  PubMed  Google Scholar 

  54. 54

    Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Eyers, P. A., Craxton, M., Morrice, N., Cohen, P. & Goedert, M. Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem. Biol. 5, 321–328 (1998).

    CAS  Google Scholar 

  56. 56

    Liu, Y. et al. Structural basis for selective inhibition of Src family kinases by PP1. Chem. Biol. 8, 257–266 (1999).

    Google Scholar 

  57. 57

    Blencke, S., Ullrich, A. & Daub, H. Mutation of threonine 766 in the epidermal growth factor receptor reveals a hotspot for resistance formation against selective tyrosine kinase inhibitors. J. Biol. Chem. 278, 15435–15440 (2003).

    CAS  Google Scholar 

  58. 58

    Stamos, J., Sliwkowski, M. X. & Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 277, 46265–46272 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Muhsin, M., Graham, J. & Kirkpatrick, P. Gefitinib. Nature Rev. Drug Discov. 2, 515–516 (2003).

    CAS  Google Scholar 

  60. 60

    Cohen, M. H. et al. United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin. Cancer Res. 10, 1212–1218 (2004).

    CAS  Google Scholar 

  61. 61

    Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004). This paper and reference 62 were the first to describe a correlation of drug-sensitizing, activating mutations in the EGFR gene with clinical responses to gefitinib in lung cancer patients.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    CAS  Google Scholar 

  63. 63

    Pao, W. et al. EGF receptor gene mutations are common in lung cancers from 'never smokers' and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).

    CAS  Google Scholar 

  64. 64

    Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004).

    CAS  Google Scholar 

  65. 65

    Cools, J. et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer Cell 3, 459–469 (2003).

    CAS  Google Scholar 

  66. 66

    Mohammadi, M. et al. Structure of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 276, 955–960 (1997).

    CAS  PubMed  Google Scholar 

  67. 67

    Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Roche-Lestienne, C., Lai, J. L., Darre, S., Facon T. & Preudhomme, C. A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. N. Engl. J. Med. 348, 2265–2266 (2003).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Hofmann, W. K. et al. Presence of the BCR–ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 102, 659–661 (2003).

    CAS  Google Scholar 

  70. 70

    Druker, B. J. Overcoming resistance to imatinib by combining targeted agents. Mol. Cancer Ther. 2, 225–226 (2003).

    CAS  Google Scholar 

  71. 71

    Hampton, T. 'Promiscuous' anticancer drugs that hit multiple targets may thwart resistance. JAMA 292, 419–22 (2004).

    CAS  Google Scholar 

  72. 72

    Morphy, R., Kay, C. & Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today 9, 641–651 (2004).

    CAS  Google Scholar 

  73. 73

    Fong, T. A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 59, 99–106 (1999).

    CAS  Google Scholar 

  74. 74

    Laird, A. D. et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4162 (2000).

    CAS  Google Scholar 

  75. 75

    Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Eskens, F. A. Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br. J. Cancer 90, 1–7 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Abrams, T. J., Lee, L. B., Murray, L. J., Pryer, N. K. & Cherrington, J. M. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol. Cancer Ther. 2, 471–478 (2003).

    CAS  Google Scholar 

  78. 78

    Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    O'Farrell, A. M. et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597–3605 (2003).

    CAS  Google Scholar 

  80. 80

    Schueneman, A. J. et al. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 63, 4009–4016 (2003).

    CAS  Google Scholar 

  81. 81

    Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bain, J., McLauchlan, H., Elliott, M. & Cohen, P. The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Godl, K. et al. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc. Natl Acad. Sci. USA 100, 15434–15439 (2003).

    CAS  Google Scholar 

  84. 84

    Brehmer, D., Godl, K., Zech, B., Wissing, J. & Daub, H. Proteome-wide identification of cellular targets affected by bisindolylmaleimide-type protein kinase C inhibitors. Mol. Cell. Proteomics 3, 490–500 (2004).

    CAS  Google Scholar 

  85. 85

    Daub, H., Godl, K., Brehmer, D., Klebl, B. & Müller, G. Evaluation of kinase inhibitor selectivity by chemical proteomics. Assay Drug. Dev. Technol. 2, 215–224 (2004).

    CAS  Google Scholar 

  86. 86

    Cheok, M. H. et al. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nature Genet. 34, 85–90 (2003).

    CAS  Google Scholar 

  87. 87

    Pack, S. D. et al. Simultaneous suppression of epidermal growth factor receptor and c-erbB-2 reverses aneuploidy and malignant phenotype of a human ovarian carcinoma cell line. Cancer Res. 64, 789–794 (2004). This interesting paper reports the reversal of aneuploidy after co-targeting of the EGFR and the closely related HER2 tyrosine kinase.

    CAS  Google Scholar 

  88. 88

    Baselga, J. & Hammond, L. A. HER-targeted tyrosine-kinase inhibitors. Oncology 63 (Suppl. 1), 6–16 (2002).

    CAS  Google Scholar 

  89. 89

    Towatari, M. et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR–ABL positive acute lymphoblastic leukemia. Blood 17 Aug 2004 (doi:182/blood-2004-04–1389)

  90. 90

    Hoover, R. R., Mahon, F. X., Melo, J. V. & Daley, G. Q. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 100, 1068–1071 (2002).

    CAS  PubMed  Google Scholar 

  91. 91

    Gorre, M. E., Ellwood-Yen, K., Chiosis, G., Rosen, N. & Sawyers, C. L. 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, 3041–3044 (2002).

    CAS  PubMed  Google Scholar 

  92. 92

    Richman, D. D. HIV chemotherapy. Nature 410, 995–1001 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to thank D. Brehmer for stimulating discussions and his contributions to the illustrations in figure 2 and figure 5. The work carried out in the laboratory of H.D. is supported by a grant from the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Henrik Daub.

Ethics declarations

Competing interests

H.D. is an employee of Axxima Pharmaceuticals AG.A.U. and H.D. are shareholders in Axxima Pharmaceuticals AG.

Related links

Related links

DATABASES

Entrez Gene

ABL

BCR

EGFR

FGFR1

FIP1L1

FLT3

insulin-like growth factor 1 receptor

Kit

Lyn

PDGFRα

PDGFRβ

P-glycoprotein

VEGFR

OMIM

CML 

Cancer.gov

Adult ALL

Glossary

CHRONIC MYELOID LEUKAEMIA

(CML). A myeloproliferative disorder that is characterized by a distinctive cytogenetic abnormality, the Philadelphia (Ph) chromosome.

BCR–ABL

The fusion gene that results from the chromosomal translocation that causes the Abelson protein tyrosine kinase gene to fuse with the BCR gene on the so-called Philadelphia (Ph) chromosome.

BLAST CRISIS

The aggressive phase of chronic myelogenous leukaemia evidenced by an increased number of immature white blood cells in the circulating blood.

INDUCED-FIT MECHANISM

The interaction between a protein and ligand in which the binding of the ligand alters the conformation of the protein's active site to best accommodate binding of the ligand.

IDIOPATHIC HYPER-EOSINOPHILIC SYNDROME

The presence of prolonged eosinophilia without an identifiable underlying cause and with evidence of end-organ dysfunction.

INTERSTITIAL CHROMOSOMAL DELETION

Loss of material from within one of the chromosome arms.

HUMAN KINOME

The collection of genes in the human genome encoding kinases.

DUAL-SPECIFICITY KINASE INHIBITOR

An inhibitor that specifically interferes with two distinct protein kinase activities.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Daub, H., Specht, K. & Ullrich, A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 3, 1001–1010 (2004). https://doi.org/10.1038/nrd1579

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing