International Journal of Clinical Oncology

, Volume 14, Issue 2, pp 143–149

Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene

Authors

    • Department of SurgeryOsaka University Graduate School of Medicine
  • Tsuyoshi Takahashi
    • Department of SurgeryOsaka University Graduate School of Medicine
  • Akiko Nishitani
    • Department of SurgeryOsaka University Graduate School of Medicine
  • Toshihiko Doi
    • Division of Gastrointestinal Oncology/Digestive EndoscopyNational Cancer Center Hospital East
  • Kuniaki Shirao
    • Department of Medical OncologyNational Cancer Center Hospital
  • Yoshito Komatsu
    • Department of GastroenterologyHokkaido University Graduate School of Medicine
  • Kiyokazu Nakajima
    • Department of SurgeryOsaka University Graduate School of Medicine
  • Seiichi Hirota
    • Department of Surgical PathologyHyogo Medical College
  • Japanese Study Group on GIST
Original Article

DOI: 10.1007/s10147-008-0822-y

Cite this article as:
Nishida, T., Takahashi, T., Nishitani, A. et al. Int J Clin Oncol (2009) 14: 143. doi:10.1007/s10147-008-0822-y

Abstract

Background

Although sunitinib malate has shown significant clinical effect on imatinib-resistant gastrointestinal stromal tumors, with acceptable tolerability and improved prognosis for the patients, the mechanism of resistance to the drug is still under investigation.

Methods

We analyzed findings in 8 patients (seven men and one woman, median age, 59 years) out of 17 patients with imatinib-resistant gastrointestinal stromal tumors who had been treated with sunitinib. Sunitinib was orally administered once a day at a starting dose of 37.5 mg/day, 50 mg/day, or 75 mg/day, with 4 weeks on and 2 weeks off.

Results

All imatinib- as well as sunitinib-resistant lesions showed viable tumor cells strongly re-expressing the KIT protein. Pre-imatinib samples had heterogeneous KIT mutations either in exon 9 (n = 1) or exon 11 (n = 7), and seven imatinib-resistant tumors carried a secondary mutation either in the ATP-binding domain or in the activation loop in the same allele as the primary mutation. Most patients with imatinib-resistant tumors carrying secondary mutations in the ATP-binding domain obtained clinical benefits from sunitinib, whereas some tumors with mutations in the activation loop showed resistance to the drug. A tumor with mutations in exon 11 and 13 of the KIT gene, and showing partial response to sunitinib, harbored a third mutation in the activation loop when sunitinib resistance was shown. All additional secondary and tertiary mutations were located on the same allele as the primary mutation (cis-mutation).

Conclusion

These findings indicate that an additional cis-mutation in the activation loop of the KIT gene could be a potential cause of sunitinib resistance in gastrointestinal stromal tumors.

Key words

Acquired resistanceKITImatinibSunitinibMutation

Copyright information

© Japan Society of Clinical Oncology 2009