Skip to main content

Advertisement

SpringerLink
Log in

Imatinib resistance in gastrointestinal stromal tumors

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are 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

Similar content being viewed by others

References

  1. 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.

    Article  PubMed  CAS  Google Scholar 

  2. Koh JS, Trent J, Chen L, et al.: Gastrointestinal stromal tumors: overview of pathologic features, molecular biology, and therapy with imatinib mesylate. Histol Histopathol 2004, 19:565–574.

    PubMed  CAS  Google Scholar 

  3. Antonescu, CR, Sommer G, Sarran L, et al.: Association of KIT exon 9 mutation with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 2003, 9:3329–3337.

    PubMed  CAS  Google Scholar 

  4. Taniguchi M, Nishida T, Hirota S, et al.: Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 1999, 59:4297–4300.

    PubMed  CAS  Google Scholar 

  5. Sandberg AA, Bridge JA: Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: gastrointestinal stromal tumors. Cancer Genet Cytogenet 2002, 135:1–22.

    Article  PubMed  CAS  Google Scholar 

  6. Heinrich MC, Corless CL, Demetri GD, et al.: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003, 21:4342–4349. The US-Finland Collaborative GIST Study Group, in a phase II clinical trial, evaluated the effect of imatinib in 127 patients with advanced GISTs. Activation mutations of KIT or PDGFRA were found in 112 (88.2%) and 6 (4.7%), respectively. The mutational status of KIT or PDGFRA is predictive of clinical response to imatinib.

    Article  PubMed  CAS  Google Scholar 

  7. Heinrich MC, Corless CL, Deunsing A, et al.: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003, 299:708–710.

    Article  PubMed  CAS  Google Scholar 

  8. Hirota S, Ohashi A, Nishida T, et al.: Gain-of-function mutations of platelet-derived growth factor receptor a gene in gastrointestinal stromal tumors. Gastroenterology 2003, 125:660–667.

    Article  PubMed  CAS  Google Scholar 

  9. Manley PW, Cowan-Jacob SW, Buchdunger E, et al.: Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer 2002, 38:S19-S27.

    Article  PubMed  Google Scholar 

  10. van Oosterom AT, Judson I, Verweij J, et al.: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001, 358:1421–1423.

    Article  PubMed  Google Scholar 

  11. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002, 347:472–480.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Mol CD, Dougan DR, Schneider TR, et al.: Structural basis for the autoinhibition and STI-571 inhibition of c-kit tyrosine kinase. J Biol Chem 2004, 279:31655–31663. This study provides a three-dimensional structural basis for understanding KIT kinase autoinhibition and imatinib inhibition of KIT tyrosine kinase.

    Article  PubMed  CAS  Google Scholar 

  14. Debiec-Rychter M, Dumez H, Judson I, et al.: Use of c-KIT/ PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004, 40:689–695. Patients with GISTs harboring exon 11 mutations were more likely to achieve a partial response on imatinib therapy (83%) than all of the others (23%).

    Article  PubMed  CAS  Google Scholar 

  15. Heinrich MC, Shoemaker JS, Corless CL, et al.: Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+) [abstract]. Proc ASCO 2005, 24:7.

    Google Scholar 

  16. Blackstein ME, Rankin C, Fletcher C, et al.: Clinical benefit of imatinib in patients (pts) with metastatic gastrointestinal stromal tumors (GIST) negative for the expression of CD117 in the S0033 trial [abstract]. Proc ASCO 2005, 24:9010.

    Google Scholar 

  17. Chen LL, Trent JC, Wu EF, et al.: A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 2004, 64:5913–5919. Six rapidly progressive imatinib-resistant implants from five GIST patients showed an identical novel KIT missense mutation, 1982T≥C, resulting in the replacement of Val at codon 654 with Ala (V654A) in the KIT tyrosine kinase domain 1. This novel mutation is strongly correlated with imatinib resistance.

    Article  PubMed  CAS  Google Scholar 

  18. Tamborini E, Bonadiman L, Greco A, et al.: A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004, 127:294–299. A single case report of a second new mutation in KIT confers imatinib resistance. It is a missense mutation, 2030C→T, in exon 14 of KIT, resulting in replacement of Thr at codon 670 by Ile (T670I), in addition to the first exon 11 activation mutation,.

    Article  PubMed  CAS  Google Scholar 

  19. Wakai T, Kanda T, Hirota S, et al.: Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br J Cancer 2004, 90:2059–2061. A case report of a new second mutation in exon 17 of KIT resulting in replacement of Tyr at codon 823 by Asp (Y823D), in addition to the initial exon 11 activation mutation in KIT, in a single case of acquired imatinib-resistant GIST.

    PubMed  CAS  Google Scholar 

  20. Nardi V, Azam M, Daley GQ: Mechanisms and implications of imatinib resistance mutations in BCR-ABL. Curr Opin Hematol 2004, 11:35–43.

    Article  PubMed  CAS  Google Scholar 

  21. Tauchi T, Ohyashiki K: Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk Res 2004, 28(Suppl 1):S39-S45.

    Article  PubMed  CAS  Google Scholar 

  22. Tosoni A, Nicolardi L, Brandes AA: Current clinical management of gastrointestinal stromal tumors. Expert Rev Anticancer Ther 2004, 4:595–605. This review article covers epidemiology, clinical presentation, pathology, molecular biology, imatinib resistance, and treatment of GISTs.

    Article  PubMed  CAS  Google Scholar 

  23. Choi H, Charnsangavej C, Faria S, et al.: Correlation of computed tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate: time to re-visit tumor response criteria. J Clin Oncol, in press.

  24. Guex N, Peitsch MC: SWISS-MODEL and the Swiss-Pdb-Viewer: an environment for comparative protein modeling. Electrophoresis 1997, 18:2714–2723.

    Article  PubMed  CAS  Google Scholar 

  25. Andtbacka RHI, Ng CS, Cormier JN, et al.: Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Presented at the meeting of the Society of Surgical Oncology, Atlanta, GA, March 3–6, 2005.

  26. Antoch G, Kanja J, Bauer S, et al.: Comparison of PET, CT and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004, 45:357–365.

    PubMed  CAS  Google Scholar 

  27. Rankin C, Von Mehren M, Blanke C, et al.: Dose effect of imatinib (IM) in patients (pts) with metastatic GIST-Phase III Sarcoma Group Study S0033. J Clin Oncol 2004, 22:9005.

    Google Scholar 

  28. Zalcberg JR, Verweij J, Casali PG, et al.: Outcome of patients with advanced gastro-intestinal stromal tumors (GIST) crossing over to a daily imatinib dose of 800 mg (HD) after progression on 400 mg (LD): an international, Intergroup study of the EORTC, ISG and AGITG [abstract]. J Clin Oncol 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition), 22:9004.

  29. Verweij J, Casali PG, Zalcberg J, et al.: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004, 364:1127–1134. Nine hundred forty-six GIST patients were randomized to imatinib, 400 mg once or twice a day, and the response rate and progression-free survival were examined at a median follow-up of 760 days. There was no difference in response rate between the two groups; however, a dosage of 400 mg twice a day achieved significantly longer progression-free survival.

    Article  PubMed  CAS  Google Scholar 

  30. Mudan SS, Conlon KC, Woodruff JM, et al.: Salvage surgery for patients with recurrent gastrointestinal sarcoma. Cancer 2000, 88:66–74.

    Article  PubMed  CAS  Google Scholar 

  31. Demetri GD, Desai J, Fletcher JA, et al.: SU11248, a multitargeted 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, 22:3001.

    Google Scholar 

  32. Maki, RG, Fletcher JA, Heinrich MC, et al.: Results from a continuation trial of SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) [abstract]. Proc ASCO 2005, 24:9011.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Sarcoma, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, 77030, Houston, TX, USA

    Lei L. Chen MD, PhD, Mahyar Sabripour PhD, Robert H. I. Andtbacka MD, Shreyaskumar R. Patel MD, Barry W. Feig MD, Homer A. Macapinlac MD, Haesun Choi MD, Elsie F. Wu MS, Marsha L. Frazier PhD & Robert S. Benjamin MD

Authors
  1. Lei L. Chen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahyar Sabripour PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert H. I. Andtbacka MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shreyaskumar R. Patel MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barry W. Feig MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Homer A. Macapinlac MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haesun Choi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elsie F. Wu MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marsha L. Frazier PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Robert S. Benjamin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, L.L., Sabripour, M., Andtbacka, R.H.I. et al. Imatinib resistance in gastrointestinal stromal tumors. Curr Oncol Rep 7, 293–299 (2005). https://doi.org/10.1007/s11912-005-0053-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-005-0053-6

Keywords

Search

Navigation