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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 Cancer science
Vol 99
Issue 4
Date 2008 Apr
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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT D820V missense unknown KIT D820V lies within the protein kinase domain of the Kit protein (UniProt.org). D820V has been identified as a secondary mutation associated with imatinib resistant (PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Apr 2020). Y
KIT K558N missense unknown KIT K558N lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). K558N has been identified in sequencing studies (PMID: 21326036, PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jun 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT W557_K558del KIT D816E KIT D820V gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT D816E and D820V were identified as secondary mutations in a patient with gastrointestinal stromal tumor harboring KIT W557_K558del who developed resistance to Gleevec (imatinib) (PMID: 18294292). 18294292