Skip to main content

Advertisement

SpringerLink
Log in

Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor

  • Supplement (Special Issue)
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60 months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9–14% of patients have progression within 3 months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24 months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R et al (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61(22):8118–8121

    CAS  PubMed  Google Scholar 

  2. Duensing A, Heinrich MC, Fletcher CD, Fletcher JA (2004) Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest 22(1):106–116

    Article  CAS  PubMed  Google Scholar 

  3. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152(5):1259–1269

    CAS  PubMed  Google Scholar 

  4. Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A (1995) W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373(6512):347–349

    Article  CAS  PubMed  Google Scholar 

  5. Nocka K, Majumder S, Chabot B, Ray P, Cervone M, Bernstein A et al (1989) Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice–evidence for an impaired c-kit kinase in mutant mice. Genes Dev 3(6):816–826

    Article  CAS  PubMed  Google Scholar 

  6. Besmer P, Murphy JE, George PC, Qiu FH, Bergold PJ, Lederman L et al (1986) A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320(6061):415–421

    Article  CAS  PubMed  Google Scholar 

  7. Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ et al (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6(11):3341–3351

    CAS  PubMed  Google Scholar 

  8. Miettinen M, Sobin LH, Sarlomo-Rikala M (2000) Immunohistochemical spectrum of GIST at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 13(10):1134–1142

    Article  CAS  PubMed  Google Scholar 

  9. Isozaki K, Hirota S, Miyagawa J, Taniguchi M, Shinomura Y, Matsuzawa Y (1997) Deficiency of c-kit + cells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction. Am J Gastroenterol 92(2):332–334

    CAS  PubMed  Google Scholar 

  10. Isozaki K, Hirota S, Nakama A, Miyagawa J, Shinomura Y, Xu Z et al (1995) Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats. Gastroenterology 109(2):456–464

    Article  CAS  PubMed  Google Scholar 

  11. Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC et al (2004) KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 28(7):889–894

    Article  PubMed  Google Scholar 

  12. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279(5350):577–580

    Article  CAS  PubMed  Google Scholar 

  13. Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda H et al (1995) Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood 85(3):790–798

    CAS  PubMed  Google Scholar 

  14. Bergmann F, Gunawan B, Hermanns B, Hoer J, Schumpelick V, Fuzesi L (1998) Cytogenetic and morphologic characteristics of gastrointestinal stromal tumors. Recurrent rearrangement of chromosome 1 and losses of chromosomes 14 and 22 as common anomalies. Verh Dtsch Ges Pathol 82:275–278

    CAS  PubMed  Google Scholar 

  15. Debiec-Rychter M, Lasota J, Sarlomo-Rikala M, Kordek R, Miettinen M (2001) Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation. Cancer Genet Cytogenet 128(1):24–30

    Article  CAS  PubMed  Google Scholar 

  16. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33(5):484–495

    Article  CAS  PubMed  Google Scholar 

  17. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N et al (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299(5607):708–710

    Article  CAS  PubMed  Google Scholar 

  18. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P et al (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23):5357–5364

    Article  CAS  PubMed  Google Scholar 

  19. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934

    Article  CAS  PubMed  Google Scholar 

  20. Kitamura Y, Hirotab S (2004) Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 61(23):2924–2931

    Article  CAS  PubMed  Google Scholar 

  21. Nocka K, Buck J, Levi E, Besmer P (1990) Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors. EMBO J 9(10):3287–3294

    CAS  PubMed  Google Scholar 

  22. Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN et al (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279(30):31655–31663

    Article  CAS  PubMed  Google Scholar 

  23. Mol CD, Lim KB, Sridhar V, Zou H, Chien EY, Sang BC et al (2003) Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem 278(34):31461–31464

    Article  CAS  PubMed  Google Scholar 

  24. Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S et al (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GIST). Oncogene 23(22):3999–4006

    Article  CAS  PubMed  Google Scholar 

  25. Taylor ML, Metcalfe DD (2000) Kit signal transduction. Hematol Oncol Clin North Am 14(3):517–535

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Z, Zhang R, Joachimiak A, Schlessinger J, Kong XP (2000) Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Proc Natl Acad Sci USA 97(14):7732–7737

    Article  CAS  PubMed  Google Scholar 

  27. Gramza AW, Corless CL, Heinrich MC (2009) Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors. Clin Cancer Res 15(24):7510–7518

    Article  CAS  PubMed  Google Scholar 

  28. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295(1):139–145

    CAS  PubMed  Google Scholar 

  29. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2(5):561–566

    Article  CAS  PubMed  Google Scholar 

  30. Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20(36):5054–5058

    Article  CAS  PubMed  Google Scholar 

  31. Roskoski R Jr (2005) Structure and regulation of Kit protein-tyrosine kinase–the stem cell factor receptor. Biochem Biophys Res Commun 338(3):1307–1315

    Article  CAS  PubMed  Google Scholar 

  32. Fantl WJ, Johnson DE, Williams LT (1993) Signalling by receptor tyrosine kinases. Annu Rev Biochem 62:453–481

    CAS  PubMed  Google Scholar 

  33. Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241(4861):42–52

    Article  CAS  PubMed  Google Scholar 

  34. Mol CD, Fabbro D, Hosfield DJ (2004) Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors. Curr Opin Drug Discov Devel 7(5):639–648

    CAS  PubMed  Google Scholar 

  35. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344(14):1052–1056

    Article  CAS  PubMed  Google Scholar 

  36. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S et al (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358(9291):1421–1423

    Article  PubMed  Google Scholar 

  37. van Oosterom AT, Judson IR, Verweij J, Stroobants S, Dumez H, di Paola ED et al (2002) Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38(Suppl 5):S83–S87

    Article  PubMed  Google Scholar 

  38. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480

    Article  CAS  PubMed  Google Scholar 

  39. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA et al (2008) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26(4):620–625

    Article  CAS  PubMed  Google Scholar 

  40. Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G et al (2002) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8(10):3034–3038

    CAS  PubMed  Google Scholar 

  41. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS et al (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26(4):626–632

    Article  CAS  PubMed  Google Scholar 

  42. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364(9440):1127–1134

    Article  CAS  PubMed  Google Scholar 

  43. Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY et al (2005) Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41(12):1751–1757

    Article  CAS  PubMed  Google Scholar 

  44. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349

    Article  CAS  PubMed  Google Scholar 

  45. Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42(8):1093–1103

    Article  CAS  PubMed  Google Scholar 

  46. Sciot R, Debiec-Rychter M, Daugaard S, Fisher C, Collin F, van Glabbeke M et al (2008) Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GIST): An analysis of the EORTC phase III trial of treatment of metastatic GIST with imatinib mesylate. Eur J Cancer 44(13):1855–1860

    Article  PubMed  Google Scholar 

  47. Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CD et al (2008) Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by cancer and leukemia group B and Southwest oncology group. J Clin Oncol 26(33):5360–5367

    Google Scholar 

  48. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28(7):1247–1253

    Google Scholar 

  49. Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I et al (2005) Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 23(24):5795–5804

    Google Scholar 

  50. Sleijfer S, Wiemer E, Seynaeve C, Verweij J (2007) Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. Oncologist 12(6):719–726

    Article  CAS  PubMed  Google Scholar 

  51. Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ et al (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24(29):4764–4774

    Article  CAS  PubMed  Google Scholar 

  52. Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP et al (2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47(10):853–859

    Article  CAS  PubMed  Google Scholar 

  53. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD et al (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27(19):3141–3147

    Article  CAS  PubMed  Google Scholar 

  54. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11(11):4182–4190

    Article  CAS  PubMed  Google Scholar 

  55. Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D et al (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26(33):5352–5359

    Article  CAS  PubMed  Google Scholar 

  56. Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC et al (2008) Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216(1):64–74

    Article  CAS  PubMed  Google Scholar 

  57. Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12(6):1743–1749

    Article  CAS  PubMed  Google Scholar 

  58. Conca E, Negri T, Gronchi A, Fumagalli E, Tamborini E, Pavan GM et al (2009) Activate and resist: L576P-KIT in GIST. Mol Cancer Ther 8(9):2491–2495

    Article  CAS  PubMed  Google Scholar 

  59. Blay JY (2010) Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib. Ann Oncol 21(2):208–215

    Article  PubMed  Google Scholar 

  60. O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW et al (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101(9):3597–3605

    Article  PubMed  Google Scholar 

  61. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G et al (2003) 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(1):327–337

    Google Scholar 

  62. Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schoffski P et al (2006) Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12(8):2622–2627

    Article  CAS  PubMed  Google Scholar 

  63. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N et al (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24(1):25–35

    Article  CAS  PubMed  Google Scholar 

  64. Demetri GD DJ, Fletcher JA, Morgan JA, Fletcher CD, Kazanovicz A, Van Den Abbeele A, Baum C, Maki R, Heinrich MC (2004) SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST). J Clin Oncol. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition), vol 22, No 14S (July 15 Supplement) 3001

  65. Deprimo SE, Huang X, Blackstein ME, Garrett CR, Harmon CS, Schoffski P et al (2009) Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res 15(18):5869–5877

    Google Scholar 

  66. George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE et al (2009) Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 45(11):1959–1968

    Google Scholar 

  67. Guo T, Hajdu M, Agaram NP, Shinoda H, Veach D, Clarkson BD et al (2009) Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res 15(22):6862–6870

    Google Scholar 

  68. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7(2):129–141

    Google Scholar 

  69. Prenen H, Guetens G, de Boeck G, Debiec-Rychter M, Manley P, Schoffski P et al (2006) Cellular uptake of the tyrosine kinase inhibitors imatinib and AMN107 in gastrointestinal stromal tumor cell lines. Pharmacology 77(1):11–16

    Article  CAS  PubMed  Google Scholar 

  70. Von Mehren MRP, Casali PG, Blay J, Debiec-Rychter M, Dumez M, Cheung W, Feifel B, Veronese M and Demetri GD (2007) A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)—Study update. Abstract: 10023. In: ASCO Annual Meeting 2007

  71. Sevinc A (2009) Activity of nilotinib (AMN-107) alone in advanced gastrointestinal stromal tumors progressing on imatinib and sunitinib. Case report. Chemotherapy 55(2):132–136

    Google Scholar 

  72. Reichardt P CP, Blay J, Von Mehren M, Schoffski P, Hosseinzadeh S, Tanaka C, Gsponer T, Veronese ML, Demetri GD (2006) A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST). J Clin Oncol. 2006 ASCO Annual Meeting Proceedings Part I, vol 24, No 18S (June 20 Supplement), 9545 2006 ASCO Annual Meeting. Abstract 9545

  73. Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609

    Article  CAS  PubMed  Google Scholar 

  74. Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY et al (2006) Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 66(1):473–481

    Article  CAS  PubMed  Google Scholar 

  75. Demetri GD, Lo Russo P, MacPherson IR, Wang D, Morgan JA, Brunton VG et al (2009) Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 15(19):6232–6240

    Article  CAS  PubMed  Google Scholar 

  76. Lyons JF, Wilhelm S, Hibner B, Bollag G (2001) Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 8(3):219–225

    Article  CAS  PubMed  Google Scholar 

  77. Wilhelm S, Chien DS (2002) BAY 43–9006: preclinical data. Curr Pharm Des 8(25):2255–2257

    Article  CAS  PubMed  Google Scholar 

  78. Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM et al (2007) Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res 13(11):3363–3369

    Article  CAS  PubMed  Google Scholar 

  79. Guo T, Agaram NP, Wong GC, Hom G, D’Adamo D, Maki RG et al (2007) Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 13(16):4874–4881

    Article  CAS  PubMed  Google Scholar 

  80. Wiebe L, Kasza K, Maki RG (2008) Sorafenib is active in patients with imatinib and sunitinib-resistant gastrointestinal stromal tumors (GIST): a phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol 26, 553 s Abstract 10502

    Google Scholar 

  81. Maki RG, D’Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD et al (2009) Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 27(19):3133–3140

    Article  CAS  PubMed  Google Scholar 

  82. Reichardt P, Montemurro M, Gelderblom H, Blay J et al (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). J Clin Oncol 28(7):1247–1253

    Google Scholar 

  83. Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Casteran N et al (2009) Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 4(9):e7258

    Article  PubMed  Google Scholar 

  84. Soria JC, Massard C, Magne N, Bader T, Mansfield CD, Blay JY et al (2009) Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers. Eur J Cancer 45(13):2333–2341

    Article  CAS  PubMed  Google Scholar 

  85. Le Cesne A, Blay JY, Bui BN, Bouche O, Adenis A, Domont J et al (2010) Phase II study of oral masitinib mesilate in imatinib-naive patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). Eur J Cancer 46(8):1344–1351

    Article  CAS  PubMed  Google Scholar 

  86. Drevs J, Hofmann I, Hugenschmidt H, Wittig C, Madjar H, Muller M et al (2000) Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60(17):4819–4824

    CAS  PubMed  Google Scholar 

  87. Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L et al (2005) Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23(18):4162–4171

    Article  CAS  PubMed  Google Scholar 

  88. Mross K, Drevs J, Muller M, Medinger M, Marme D, Hennig J et al (2005) Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41(9):1291–1299

    Article  CAS  PubMed  Google Scholar 

  89. Joensuu H, De Braud F, Coco P, De Pas T, Putzu C, Spreafico C et al (2008) Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate. Ann Oncol 19(1):173–177

    Article  CAS  PubMed  Google Scholar 

  90. Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100(10):1523–1529

    Article  CAS  PubMed  Google Scholar 

  91. Nakatani H, Kobayashi M, Jin T, Taguchi T, Sugimoto T, Nakano T et al (2005) STI571 (Glivec) inhibits the interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1. Cancer Sci 96(2):116–119

    Article  CAS  PubMed  Google Scholar 

  92. Bauer S, Yu LK, Demetri GD, Fletcher JA (2006) Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66(18):9153–9161

    Article  CAS  PubMed  Google Scholar 

  93. Li CF, Huang WW, Wu JM, Yu SC, Hu TH, Uen YH et al (2008) Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res 14(23):7822–7831

    Article  CAS  PubMed  Google Scholar 

  94. Wagner AJ, Morgan JA, Chugh R (2008) Results from phase 1 trial of IPI-504, a novel HSP90 inhibitor, in tyrosine kinase inhibitor-resistant GIST and other sarcomas. Journal of Clinical Oncology, 26, 553 s Abstract 10503

    Google Scholar 

  95. Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27(32):5459–5468

    Article  CAS  PubMed  Google Scholar 

  96. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV et al (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18(5):601–607

    Article  CAS  PubMed  Google Scholar 

  97. Liu Y, Tseng M, Perdreau SA, Rossi F, Antonescu C, Besmer P et al (2007) Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res 67(6):2685–2692

    Article  CAS  PubMed  Google Scholar 

  98. Muhlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G et al (2009) Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors. Cancer Res 69(17):6941–6950

    Article  PubMed  Google Scholar 

  99. Floris G, Debiec-Rychter M, Sciot R, Stefan C, Fieuws S, Machiels K et al (2009) High efficacy of panobinostat towards human gastrointestinal stromal tumors in a xenograft mouse model. Clin Cancer Res 15(12):4066–4076

    Article  CAS  PubMed  Google Scholar 

  100. Bauer S, Parry JA, Muhlenberg T, Brown MF, Seneviratne D, Chatterjee P et al (2010) Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells. Cancer Res 70(1):150–159

    Article  CAS  PubMed  Google Scholar 

  101. Van Oosterom AT DH, Desai J, Stroobants S, Van Den Abbeele AD, Clement P, Shand N, Kovarik J, Tsyrlova A, Demetri GD (2004) Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I, vol 24, No 18S (June 20 Supplement), 2006: 9545

  102. Dumez H, Reichard P. Blay JY (2008) A phase I-II study of everolimus (RAD001) in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST). CRAD001C2206 Study Group. J Clin Oncol, 26, 557 s Abstract 10519

    Google Scholar 

  103. Fabbro D, Ruetz S, Bodis S, Pruschy M, Csermak K, Man A et al (2000) PKC412–a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des 15(1):17–28

    CAS  PubMed  Google Scholar 

  104. Debiec-Rychter M, Cools J, Dumez H, Sciot R, Stul M, Mentens N et al (2005) Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128(2):270–279

    Article  CAS  PubMed  Google Scholar 

  105. Reichardt P PD, Lindner T, Heinrich MC, Cohen PS, Wang Y, Yu R, Tsyrlova A, Dimitrijevic S, Blanke C (2005) A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM. J Clin Oncol. 2005 ASCO Annual Meeting Proceedings, vol 23, No 16S, Part I of II (June 1 Supplement), 3016

  106. Palassini E FE, Coco P, Piovesan C, Dileo P, Bertulli R, Casali PG (2008) Combination of PKC412 and sirolimus in a metastatic patient with PDGFRA-D842 V gastrointestinal stromal tumor (GIST). J Clin Oncol 26 (May 20 suppl; abstr 21515)

  107. Trent JC, Ramdas L, Dupart J, Hunt K, Macapinlac H, Taylor E et al (2006) Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor. Cancer 107(8):1898–1908

    Article  CAS  PubMed  Google Scholar 

  108. Pantaleo MA, Astolfi A, Di Battista M, Heinrich MC, Paterini P, Scotlandi K et al (2009) Insulin-like growth factor 1 receptor expression in wild-type GIST: a potential novel therapeutic target. Int J Cancer 125(12):2991–2994

    Article  CAS  PubMed  Google Scholar 

  109. Braconi C, Bracci R, Bearzi I, Bianchi F, Sabato S, Mandolesi A et al (2008) Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann Oncol 19(7):1293–1298

    Article  CAS  PubMed  Google Scholar 

  110. Steigen SE, Schaeffer DF, West RB, Nielsen TO (2009) Expression of insulin-like growth factor 2 in mesenchymal neoplasms. Mod Pathol 22(7):914–921

    Article  CAS  PubMed  Google Scholar 

  111. Bolland M, Benn D, Croxson M, McCall J, Shaw JF, Baillie T et al (2006) Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma. ANZ J Surg 76(8):763–764

    Article  PubMed  Google Scholar 

  112. Neumann HP, Erlic Z (2008) Maternal transmission of symptomatic disease with SDHD mutation: fact or fiction? J Clin Endocrinol Metab 93(5):1573–1575

    Article  CAS  PubMed  Google Scholar 

  113. McWhinney SR, Pasini B, Stratakis CA (2007) Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357(10):1054–1056

    Article  CAS  PubMed  Google Scholar 

  114. Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M et al (2008) Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16(1):79–88

    Article  CAS  PubMed  Google Scholar 

  115. Janeway KA LB, Nose V, Hornick JL, Barretina J, Dahia PL, Fletcher JA (2009) Complete loss of succinate dehydrogenase b (SDHB) in pediatric gastrointestinal stromal tumors. Connective Tissue Oncology Society, abstract 39408

Download references

Acknowledgments

This research is supported by NCI grants CA47179, CA148260, NCI-ASCO Cancer Foundation Clinical Investigator Team Leadership Supplemental Award, Cycle for Survival, Shuman Fund for GIST Research. Logistical support during submission of this article was provided by Springer Healthcare LLC. This support was funded by Novartis.

Conflict of interest

Dr. Mrinal M. Gounder: None. Dr. Robert G. Maki (Advisory board: Novartis, Bayer; Research support Pfizer, Roche).

Author information

Authors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mrinal M. Gounder & Robert G. Maki

Authors
  1. Mrinal M. Gounder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert G. Maki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert G. Maki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gounder, M.M., Maki, R.G. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor. Cancer Chemother Pharmacol 67 (Suppl 1), 25–43 (2011). https://doi.org/10.1007/s00280-010-1526-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1526-3

Keywords

Search

Navigation