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Ref Type Journal Article
PMID (18294292)
Authors Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, Hirota S
Title Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor.
Journal Vol Issue Date Pages Journal Short Title
Cancer science 99 4 2008 Apr 799-804 Cancer Sci
URL
Abstract Text Although imatinib showed high activity for advanced gastrointestinal stromal tumor (GIST) and improved the prognosis of GIST patients, resistance to the drug appears with prolonged use. Mechanisms of acquired resistance are still under investigation. In the present study, we carried out histologic and genetic analysis of 45 secondary resistant lesions obtained from 25 Japanese GIST patients treated with imatinib. All resistant lesions showed viable tumor cells expressing KIT protein, whereas imatinib-sensitive lesions did not. All pre-imatinib samples have KIT mutations either in exon 9 (n = 3) or exon 11 (n = 22), identified in the KIT gene of corresponding resistant tumors. In addition to primary mutations, 33 out of 45 tumors (73%) showed secondary KIT mutations in the kinase domain of the KIT gene. Secondary mutations are missense mutations and are mostly located in the kinase domains of the same allele to the primary mutations (cis-position). Resistant lesions showed monoclonal development of tumor cells. Taken together, additional cis-positioned mutations in the kinase domains are a major cause of secondary resistance to imatinib in Japanese GIST patients.

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