Open AccessSecondary mutations in the kinase domain of the KIT gene are predominant in imatinib‐resistant gastrointestinal stromal tumor
Author(s) -
Nishida Toshirou,
Kanda Tatsuo,
Nishitani Akiko,
Takahashi Tsuyoshi,
Nakajima Kiyokazu,
Ishikawa Takashi,
Hirota Seiichi
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00727.x
Subject(s) - gist , imatinib , stromal tumor , missense mutation , cancer research , exon , mutation , protein kinase domain , imatinib mesylate , stromal cell , gene mutation , medicine , biology , gene , pathology , genetics , mutant , myeloid leukemia
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. ( Cancer Sci 2008; 99: 799–804)