Medical Oncology

, 30:522 | Cite as

Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors

  • Jing Gao
  • Ye Tian
  • Jian Li
  • Naiping Sun
  • Jiajia Yuan
  • Lin Shen
Original Paper

Abstract

The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRα and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRα (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRα mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P < 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated.

Keywords

c-KIT Secondary mutation Acquired resistance Imatinib Sunitinib 

Notes

Acknowledgments

This work was supported by Beijing Municipal Natural Science Foundation (No. 7122031). We thank Dr. Jiping Yue (Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon, France) and Professor Sonya W Song (Clinical Research Laboratory of Peking University Cancer Hospital and Institute, Beijing, China) for critical reading of this manuscript.

Conflict of interest

None.

References

  1. 1.
    Min KW, Leabu M. Interstitial Cells of Cajal (ICC) and Gastrointestinal Stromal Tumor (GIST): facts, speculations, and myths. J Cell Mol Med. 2006;10:995–1013.CrossRefPubMedGoogle Scholar
  2. 2.
    Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093–103.CrossRefPubMedGoogle Scholar
  3. 3.
    Kim TW, Ryu MH, Lee H, et al. Kinase mutations and efficacy of imatinib in Korean patients with advanced gastrointestinal stromal tumors. Oncologist. 2009;14:540–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10.CrossRefPubMedGoogle Scholar
  5. 5.
    Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–64.CrossRefPubMedGoogle Scholar
  6. 6.
    Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol. 2004;11:465–75.CrossRefPubMedGoogle Scholar
  7. 7.
    Buchdunger E, Cioffi CL, Law N, et al. 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;295:139–45.PubMedGoogle Scholar
  8. 8.
    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;358:1421–3.CrossRefPubMedGoogle Scholar
  9. 9.
    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;347:472–80.CrossRefPubMedGoogle Scholar
  10. 10.
    Blanke CD, Rankin C, Demetri GD, et al. 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. 2008;26:626–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–90.CrossRefPubMedGoogle Scholar
  13. 13.
    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. 2010;136:1065–71.CrossRefPubMedGoogle Scholar
  14. 14.
    Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib: a randomized controlled trial. Lancet. 2006;368(9544):1329–38.CrossRefPubMedGoogle Scholar
  15. 15.
    Li J, Gao J, Hong JL, et al. Efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant. Future Oncol. 2012;8(5):617–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Cajiwala KS, Wu JC, Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci USA. 2009;106(5):1542–7.CrossRefGoogle Scholar
  17. 17.
    DiNitto JP, Deshmukh GD, Zhang Y, et al. Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit autoactivation and its implication in sunitinib resistance. J Biochem. 2010;147(4):601–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26(33):5352–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Hong JL, Li J, Li J, et al. Secondary mutations of c-kit/PDGFRα genotypes after imatinib mesylate therapy and its relationship with efficacy of sunitinib. Chin J Pathol. 2012;41(6):386–90.Google Scholar
  20. 20.
    Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34.CrossRefPubMedGoogle Scholar
  22. 22.
    Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Tzen CY, Wang MN, Mau BL. Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors. Eur J Surg Oncol. 2008;34:563–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Lennartsson J, Jelacic T, Linnekin D, et al. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005;23:16–43.CrossRefPubMedGoogle Scholar
  25. 25.
    Miselli FC, Casieri P, Negri T, et al. KIT/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:2369–77.CrossRefPubMedGoogle Scholar
  26. 26.
    Wardelmann E, Büttner R, Merkelbach-Bruse S, et al. Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy. Virchows Arch. 2007;451:743–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Tornillo L, Terracciano LM. An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol. 2006;59:557–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Nishida T, Kanda T, Nishitani A, et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci. 2008;99:799–804.CrossRefPubMedGoogle Scholar
  29. 29.
    Liegl B, Kepten I, Le C, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74.CrossRefPubMedGoogle Scholar
  30. 30.
    Sápi Z, Füle T, Hajdu M, et al. The activated targets of mTOR signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs. Diagn Mol Pathol. 2011;20:22–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Rutkowski P, Bylina E, Klimczak A, et al. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure-one institution study. BMC Cancer. 2012;12:107–15.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim JJ, Vaziri SA, Rini BI, et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear renal carcinoma patients treated with sunitinib. Cancer. 2011;118(7):1946–54.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jing Gao
    • 1
  • Ye Tian
    • 1
  • Jian Li
    • 1
  • Naiping Sun
    • 1
  • Jiajia Yuan
    • 1
  • Lin Shen
    • 1
  1. 1.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI OncologyPeking University Cancer Hospital and InstituteHaidian District, BeijingChina

Personalised recommendations