Skip to main content

Advertisement

SpringerLink
Log in

Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Aims and background

Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition therapy of imatinib, but eventually become resistant with a median time to progression of 2 years. The mechanism of acquired resistance to imatinib and oncogenic KIT signal transduction in GISTs has not been well defined. We sought to investigate the spectrum of molecular and genomic changes in imatinib-resistant GIST patients.

Methods

KIT and PDGFRA mutations were evaluated in 48 samples obtained from 32 GIST patients who underwent surgery after imatinib treatment. KIT downstream signaling profiles were also investigated in eight specimens of five patients who were clinically responsive or resistant to imatinib therapy. Biochemical inhibition of KIT, mitogen-activated protein kinase (MAPK), mammalian target of rapamycin (MTOR), AKT, proliferating cell nuclear antigen (PCNA) and BCL-2 were determined by western blotting for protein activation.

Results

In all 32 GIST patients, activating mutations in the KIT gene were seen in 26 (81.3%) patients, PDGFRA gene mutations were seen in 2 (6.2%) patients and no primary mutations were found in 4 (12.5%) patients. Secondary KIT mutations were identified in 11/14 (78.6%) imatinib-acquired-resistance patients, with nine patients in KIT gene exon17, and the other two in exon 13. The expressions of p-KIT, p-AKT, PCNA and BCL-2 were higher in the samples of imatinib-resistant GISTs than those of imatinib-responsive ones. P-KIT, p-AKT expressions were higher in imatinib acquired-resistance GISTs with secondary KIT mutations than imatinib-responsive ones with primary mutation. Total KIT, MAPK, p-MAPK, p-MTOR expressions were comparable in all varied GISTs.

Conclusions

Novel additional mutations of KIT gene exon 13 or exon 17 indicate the likely mechanism of secondary resistance to imatinib. The PI3-K/AKT pathway might be more relevant than MEK/MAPK for therapeutic targeting in imatinib-resistant GIST patients with secondary mutation.

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

Similar content being viewed by others

References

  • Ali S, Ali S (2007) Role of c-kit/SCF in cause and treatment of gastro-intestinal stromal tumors (GIST). Gene 401:38–45

    Article  CAS  PubMed  Google Scholar 

  • Antonescu CR, Sommer G, Sarran L, Tschernyavsky SJ, Riedel E, Woodruff JM, Robson M, Maki R, Brennan MF, Ladanyi M, DeMatteo RP, Besmer P (2003) Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 9:3329–3337

    CAS  PubMed  Google Scholar 

  • 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 (2005a) 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 

  • 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 (2005b) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11:4182–4190

    Article  CAS  PubMed  Google Scholar 

  • Bauer S, Duensing A, Demetri GD, Fletcher JA (2007) KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26:7560–7568

    Article  CAS  PubMed  Google Scholar 

  • Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C, Larizza L (2001) Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer 92(3):657–662

    Article  CAS  PubMed  Google Scholar 

  • Carrillo R, Candia A, Rodriguez-Peralto JL, Caz V (1997) Prognostic significance of DNA ploidy and proliferative index (MIB-1 index) in gastrointestinal stromal tumors. Hum Pathol 28:160–165

    Article  CAS  PubMed  Google Scholar 

  • 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 (2004) A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64:5913–5919

    Article  CAS  PubMed  Google Scholar 

  • Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, Dimitrijevic S, Sciot R, Stul M, Vranck H, Scurr M, Hagemeijer A, van Glabbeke M, van Oosterom AT (2004) 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 40(5):689–695

    Article  CAS  PubMed  Google Scholar 

  • Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480

    Article  CAS  PubMed  Google Scholar 

  • Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, Fletcher CD, Demetri GD, Fletcher JA (2004) Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23:3999–4006

    Article  CAS  PubMed  Google Scholar 

  • Gumurdulu D, Erdogan S, Kayaselcuk F, Seydaoglu G, Parsak CK, Demircan O, Tuncer I (2007) Expression of COX-2, PCNA, Ki-67 and p53 in gastrointestinal stromal tumors and its relationship with histopathological parameters. World J Gastroenterol 13(3):426–431

    CAS  PubMed  Google Scholar 

  • Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003a) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349

    Article  CAS  PubMed  Google Scholar 

  • Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003b) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299(5607):708–710

    Article  CAS  PubMed  Google Scholar 

  • Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279(5350):577–580

    Article  CAS  PubMed  Google Scholar 

  • Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM (2000) Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol 157(5):1581–1585

    CAS  PubMed  Google Scholar 

  • Kang HJ, Nam SW, Kim H, Rhee H, Kim NG, Kim H, Hyung WJ, Noh SH, Kim JH, Yun CO, Liu ET, Kim H (2005) Correlation of KIT and platelet-derived growth factor receptor-α mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene 24:1066–1074

    Article  CAS  PubMed  Google Scholar 

  • Kindblom LG, Meis-Kindblom JM, Bumming P (2002) Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST)—a population-based study of 600 cases. Ann Oncol 13:157

    Article  Google Scholar 

  • Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, Fletcher CD, Corless CL, Fletcher JA (2008) Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216:64–74

    Article  CAS  PubMed  Google Scholar 

  • Liu XH, Bai CG, Xie Q, Feng F, Xu ZY, Ma DL (2005) Prognostic value of KIT mutation in gastrointestinal stromal Tumors. World J Gastroenterol 11(25):3948–3952

    CAS  PubMed  Google Scholar 

  • Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, Snell GP, Zou H, Sang BC, Wilson KP (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279:31655–31663

    Article  CAS  PubMed  Google Scholar 

  • Negri T, Bozzi F, Conca E, Brich S, Gronchi A, Bertulli R, Fumagalli E, Pierotti MA, Tamborini E, Pilotti S (2009) Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs). J Pathol 217:103–112

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Matsuda H, Kitamura Y (1998) Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 19(4):323–324

    Article  CAS  PubMed  Google Scholar 

  • Nishida T, Takahashi T, Nishitani A, Doi T, Shirao K, Komatsu Y, Nakajima K, Hirota S (2009) Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol 14:143–149

    Article  CAS  PubMed  Google Scholar 

  • Rossi F, Ehlers I, Agosti V, Socci ND, Viale A, Sommer G, Yozgat Y, Manova K, Antonescu CR, Besmer P (2006) Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci USA 103(34):12843–12848

    Article  CAS  PubMed  Google Scholar 

  • Sommer G, Agosti V, Ehlers I, Rossi F, Corbacioglu S, Farkas J, Moore M, Manova K, Antonescu CR, Besmer P (2003) Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA 100(11):6706–6711

    Article  CAS  PubMed  Google Scholar 

  • Steinert DM, Oyarzo M, Wang X, Choi H, Thall PF, Medeiros LJ, Raymond AK, Benjamin RS, Zhang W, Trent JC (2006) Expression of Bcl-2 in gastrointestinal stromal tumors correlation with progression-free survival in 81 patients treated with imatinib mesylate. Cancer 106(7):1617–1623

    Article  PubMed  Google Scholar 

  • Subramanian S, West RB, Corless CL, Ou W, Rubin BP, Chu KM, Leung SY, Yuen ST, Zhu S, Hernandez-Boussard T, Montgomery K, Nielsen TO, Patel RM, Goldblum JR, Heinrich MC, Fletcher JA, van de Rijn M (2004) Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles. Oncogene 23:7780–7790

    Article  CAS  PubMed  Google Scholar 

  • Therasse P (2002) Measuring the clinical response. What does it mean? Eur J Cancer 38:1817–1823

    Article  CAS  PubMed  Google Scholar 

  • Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I (2004) Progression free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abdominal Department, Cancer Hospital, Fudan University, 270 Dong’an Road, 200032, Shanghai, People’s Republic of China

    Chun-Meng Wang, Kai Huang, Ye Zhou, Chun-Yan Du, Yan-Wei Ye, Hong Fu & Ying-Qiang Shi

  2. Pathology Department, Cancer Hospital, Fudan University, 270 Dong’an Road, 200032, Shanghai, People’s Republic of China

    Xiao-Yan Zhou

  3. Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong’an Road, 200032, Shanghai, People’s Republic of China

    Chun-Meng Wang, Kai Huang, Ye Zhou, Chun-Yan Du, Yan-Wei Ye, Hong Fu, Xiao-Yan Zhou & Ying-Qiang Shi

Authors
  1. Chun-Meng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ye Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Yan Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan-Wei Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ying-Qiang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ying-Qiang Shi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, CM., Huang, K., Zhou, Y. et al. Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors. J Cancer Res Clin Oncol 136, 1065–1071 (2010). https://doi.org/10.1007/s00432-009-0753-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-009-0753-7

Keywords

Search

Navigation