Imatinib Mesylate (Gleevec®) and the Emergence of Chemotherapeuticss Drug-Resistant Mutations

  • Gerald V. Denis
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Imatinib mesylate (Gleevec® Novartis) is an important, new, molecularly targeted, anti-cancer agent with clinical efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). These malignancies develop after constitutive activation of Abelson (Abl) or c-kit (CD117) tyrosine kinases, respectively; Imatinib specifically inhibits such kinase activity. Many CML and GIST patients have relapsed while on imatinib treatment, however. The emergence of resistance to imatinib chemotherapeutic intervention is in retrospect neither surprising nor insoluble. Principles previously used to develop combination chemotherapy to avoid the development of multidrug resistance in leukemias and lymphomas (and later used in developing combinations for treatment of human immunodeficiency virus infections) may prove useful in the approach to the next generation of targeted molecular therapeutics for CML. In general, multidrug protocols and agents targeted to mutation sites simultaneously are likely to have a greater chance of success than single-agent therapy.

Key Words

Imatinib mesylate Gleevec STI-571 drug resistance cancer chemotherapy chronic myelogenous leukemia gastrointestinal stromal tumor BCR-ABL c-kit stem cell factor structural biology 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (Eds). SEER Cancer Statistics Review, 1975–2002. National Cancer Institute: Bethesda, MD.Google Scholar
  2. 2.
    Deininger MW, Druker BJ. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev 2003;55:401–423.PubMedCrossRefGoogle Scholar
  3. 3.
    Nashed AL, Rao KW, Gulley ML. Clinical applications of BCR-ABL molecular testing in acute leukemia. J Mol Diagn 2003;5:63–72.PubMedGoogle Scholar
  4. 4.
    Pelz AF, Kröning H, Franke A, Wieacker P, Stumm M. High reliability and sensitivity of the bcr/ABL1 D-FISH test for the detection of BCR/ABL rearrangements. Ann Hematol 2002;81:147–153.PubMedCrossRefGoogle Scholar
  5. 5.
    Chase A, Grand F, Zhang J-G, Blackett N, Goldman M. Factors influencing false positive and negative rates of BCR-ABL fluorescence in situ hybridization. Genes Chromosomes Cancer 1997;18:246–253.PubMedCrossRefGoogle Scholar
  6. 6.
    Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 1994;83:2038–2044.PubMedGoogle Scholar
  7. 7.
    Dierov JK, Dierova R, Carroll M. BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-s phase check point. Cancer Cell 2004;5:275–285.PubMedCrossRefGoogle Scholar
  8. 8.
    Shah N, Nicoll J, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117–125.PubMedCrossRefGoogle Scholar
  9. 9.
    Savage DG, Antman KH. Imtinib mesylate – a new oral targeted therapy. N Engl J Med 2002;346:683–693.PubMedCrossRefGoogle Scholar
  10. 10.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 2000;289:1938–1942.PubMedCrossRefGoogle Scholar
  11. 11.
    Roskoski, R. Jr. Structure and regulation of Kit protein-tyrosine kinase—The stem cell factor receptor. Biochem Biophys Res Commun 2005;338:1307–1315.PubMedCrossRefGoogle Scholar
  12. 12.
    Johnson LN, Noble ME, Owen DJ. Active and inactive protein kinases: structural basis for regulation. Cell 1996;85:149–158.PubMedCrossRefGoogle Scholar
  13. 13.
    Noble MEM, Endicott JA, Johnson LN. Protein kinase inhibitors: Insights into drug design from structure. Science 2004;303:1800–1805.PubMedCrossRefGoogle Scholar
  14. 14.
    Zou X, Calame K. Signaling pathways activated by oncogenic forms of Abl tyrosine kinase. J Biol Chem 1999;274:18141–18144.PubMedCrossRefGoogle Scholar
  15. 15.
    Kharas MG, Fruman DA. ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors. Cancer Res 2005;65:2047–2053.PubMedCrossRefGoogle Scholar
  16. 16.
    Klejman A, Rushen L, Morrione A, et al. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 2002;21:5868–5876.PubMedCrossRefGoogle Scholar
  17. 17.
    Sanchez-Garcia I, Martin-Zanca D. Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras. J Mol Biol 1997;267:225–228.PubMedCrossRefGoogle Scholar
  18. 18.
    Denis GV. Bromodomain motifs and “scaffolding”? Front Biosci 2001;6:D1065–D1068.PubMedGoogle Scholar
  19. 19.
    Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL, Bhatia R. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005;105:2093–2098.PubMedCrossRefGoogle Scholar
  20. 20.
    Goldman JM, Melo JV. Chronic myeloid leukemia–advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451–1464.PubMedCrossRefGoogle Scholar
  21. 21.
    Cortes J, O’Dwyer ME. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004;18:671–684.PubMedCrossRefGoogle Scholar
  22. 22.
    Fabarius A, Giehl M, Frank O, Duesberg P, Hochhaus A, Hehlmann R, Seifarth W. Induction of centrosome and chromosome aberrations by imatinib in vitro. Leukemia 2005;19:1573–1578.PubMedCrossRefGoogle Scholar
  23. 23.
    Sharma SK, Mohan A. Multidrug-resistant tuberculosis. Indian J Med Res 2004;120:354–376.PubMedGoogle Scholar
  24. 24.
    Mayr E. The Growth of Biological Thought. Cambridge, MA: Belknap, 1982;Ch. 12:535–570.Google Scholar
  25. 25.
    Ward JR. Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis. J Rheumatol 1985;12(suppl 12):3–6.Google Scholar
  26. 26.
    Yoshida C, Melo JV. Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. Int J Hematol 2004;79:420–433.PubMedCrossRefGoogle Scholar
  27. 27.
    Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M, Pursche S, Bergemann T, Ehninger G, Schleyer E. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004;18:401–408.PubMedCrossRefGoogle Scholar
  28. 28.
    Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003;101:2368–2373.PubMedCrossRefGoogle Scholar
  29. 29.
    Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D. RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines. Exp Hematol 2005;33:767–775.PubMedCrossRefGoogle Scholar
  30. 30.
    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004;104:3739–3745.PubMedCrossRefGoogle Scholar
  31. 31.
    Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE. hOCT 1 and resistance to imatinib. Blood 2005;106:1133–1134.PubMedCrossRefGoogle Scholar
  32. 32.
    Nardi V, Azam M, Daley GQ. Mechanisms and implications of imatinib resistance mutations in BCR-ABL. Curr Opin Hematol 2004;11:35–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Gratwohl A, Hermans J. Allogeneic bone marrow transplantation for chronic myeloid leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1996;17(Suppl 3):S7–S9.PubMedGoogle Scholar
  34. 34.
    Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33:459–465.PubMedCrossRefGoogle Scholar
  35. 35.
    Daum O, Klecka J, Ferda J, et al. Gastrointestinal stromal tumor of the pancreas: case report with documentation of KIT gene mutation. Virchows Arch 2005;446:470–472.PubMedCrossRefGoogle Scholar
  36. 36.
    O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, Druker BJ. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:4500–4505.PubMedCrossRefGoogle Scholar
  37. 37.
    Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004;10:262–267.PubMedCrossRefGoogle Scholar
  38. 38.
    van der Zwan SM, DeMatteo RP. Gastrointestinal stromal tumor: 5 years later. Cancer 2005;104:1781–1788.PubMedCrossRefGoogle Scholar
  39. 39.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.PubMedCrossRefGoogle Scholar
  40. 40.
    Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA 2005;102:3395–400.PubMedCrossRefGoogle Scholar
  41. 41.
    Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs WH 3rd, Treiber DK, Patel HK, Zarrinkar PP, Lockhart DJ, Sawyers CL, Kuriyan J. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 2006;66: 1007–1014.PubMedCrossRefGoogle Scholar
  42. 42.
    Fishman AP. Gastrointestinal tract. In: Rosai J, Ed. Ackerman’s Surgical Pathology. 8th ed. St. Louis: Mosby, 1996. 645–647.Google Scholar
  43. 43.
    Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998;152:1259–1269.PubMedGoogle Scholar
  44. 44.
    Ortiz-Hidalgo C, de Leon Bojorge B, Albores-Saavedra J. Stromal tumor of the gallbladder with phenotype of interstitial cells of Cajal: a previously unrecognized neoplasm. Am J Surg Pathol 2000;24:1420–1423.PubMedCrossRefGoogle Scholar
  45. 45.
    Miettinen M, Sobin LH. Gastrointestinal stromal tumors in the appendix: a clinicopathologic and immunohistochemical study of four cases. Am J Surg Pathol 2001;25:1433–1437.PubMedCrossRefGoogle Scholar
  46. 46.
    Rubin BP. Gastrointestinal stromal tumours: an update. Histopathology 2006;48:83–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Harhun MI, Pucovsky V, Povstyan OV, Gordienko DV, Bolton TB. Interstitial cells in the vasculature. J Cell Mol Med 2005;9:232–243.PubMedCrossRefGoogle Scholar
  48. 48.
    Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-KIT in human gastrointestinal stromal tumors. Science 1998;279:577–580.PubMedCrossRefGoogle Scholar
  49. 49.
    Williams DE, Eisenman J, Baird A, et al. Identification of a ligand for the c-kit proto-oncogene. Cell 1990;63:167–174.PubMedCrossRefGoogle Scholar
  50. 50.
    Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203–212.PubMedCrossRefGoogle Scholar
  51. 51.
    Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–710.PubMedCrossRefGoogle Scholar
  52. 52.
    Mudan SS, Conlon KC, Woodruff J, Lewis J, Brennan MF. Salvage surgery in recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Cancer 2000;88:51–58.CrossRefGoogle Scholar
  53. 53.
    Edmonson J, Marks R, Buckner J, Mahoney M. Contrast of response to D-MAP + Sargramostim between patients with advance malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Proc Am Soc Clin Oncol 1999;18:541a.Google Scholar
  54. 54.
    Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, Nishikawa S. Requirement of c-kit for development of intestinal pacemaker system. Development 1992;116:369–375.PubMedGoogle Scholar
  55. 55.
    Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol 2006;533:327–340.PubMedCrossRefGoogle Scholar
  56. 56.
    Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 2004;61: 2924–2931.PubMedCrossRefGoogle Scholar
  57. 57.
    Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB. 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 2000;295:139–145.PubMedGoogle Scholar
  58. 58.
    Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res 2000;6:3319–3326.PubMedGoogle Scholar
  59. 59.
    Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96:925–932.PubMedGoogle Scholar
  60. 60.
    Chen H, Isozaki K, Kinoshita K, Ohashi A, Shinomura Y, Matsuzawa Y, Kitamura Y, Hirota S. Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors. Int J Cancer 2003;105:130–135.PubMedCrossRefGoogle Scholar
  61. 61.
    Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher C-DM, Fletcher JA, Demetri GD. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001;20:5054–5058.PubMedCrossRefGoogle Scholar
  62. 62.
    Ma Y, Zeng S, Metcalfe DD, Akin C, Dimitrijevic S, Butterfield JH, McMahon G, Longley BJ. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors: kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 2002;99:1741–1744.PubMedCrossRefGoogle Scholar
  63. 63.
    Duensing A, Medeiros F, McConarty B, et al. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 2004;23:3999–4006.PubMedCrossRefGoogle Scholar
  64. 64.
    Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, Speidel N, Pietsch T, Buettner R, Pink D, Reichardt P, Hohenberger P. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12:1743–1749.PubMedCrossRefGoogle Scholar
  65. 65.
    Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23:5357–5364.PubMedCrossRefGoogle Scholar
  66. 66.
    Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, Leversha MA, Jeffrey PD, Desantis D, Singer S, Brennan MF, Maki RG, DeMatteo RP. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005;11:4182–4190.PubMedCrossRefGoogle Scholar
  67. 67.
    Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W, Raymond AK, Prieto VG, Oyedeji CO, Hunt KK, Pollock RE, Feig BW, Hayes KJ, Choi H, Macapinlac HA, Hittelman W, Velasco MA, Patel S, Burgess MA, Benjamin RS, Frazier ML. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 2004;64: 5913–5919.PubMedCrossRefGoogle Scholar
  68. 68.
    Chen LL, Sabripour M, Andtbacka RH, Patel SR, Feig BW, Macapinlac HA, Choi H, Wu EF, Frazier ML, Benjamin RS. Imatinib resistance in gastrointestinal stromal tumors. Curr Oncol Rep 2005;7:293–299.PubMedCrossRefGoogle Scholar
  69. 69.
    Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, Bertulli R, Colecchia M, Casali PG, Pierotti MA, Pilotti S. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004;127:294–299.PubMedCrossRefGoogle Scholar
  70. 70.
    Debiec-Rychter M, Cools J, Dumez H, Sciot R, Stul M, Mentens N, Vranckx H, Wasag B, Prenen H, Roesel J, Hagemeijer A, Van Oosterom A, Marynen P. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005;128:270–279.PubMedCrossRefGoogle Scholar
  71. 71.
    Prenen H, Guetens G, de Boeck G, Debiec-Rychter M, Manley P, Schoffski P, van Oosterom AT, de Bruijn E. Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacology 2006;77:11–16.PubMedCrossRefGoogle Scholar
  72. 72.
    Theou N, Gil S, Devocelle A, Julie C, Lavergne-Slove A, Beauchet A, Callard P, Farinotti R, Le Cesne A, Lemoine A, Faivre-Bonhomme L, Emile JF. Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. Clin Cancer Res 2005;11:7593–7598.PubMedCrossRefGoogle Scholar
  73. 73.
    Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Matsuda H, Kitamura Y. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 1998;19:323–324.PubMedCrossRefGoogle Scholar
  74. 74.
    Kitamura Y, Hirota S, Nishida T. Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. Cancer Sci 2003;94:315–320.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Gerald V. Denis

There are no affiliations available

Personalised recommendations