title: Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor.
abstract: 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.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Osaka, Japan. toshin@surg1.med.osaka-u.ac.jp
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishitani
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D044466:Asian People / Q000235:genetics; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit