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Ref Type Journal Article
PMID (21475850)
Authors Wang CM, Fu H, Zhao GF, Zhou XY, Du CY, Dong RZ, Zhou Y, Shi YQ
Title Secondary resistance to imatinib in patients with gastrointestinal stromal tumors through an acquired KIT exon 17 mutation.
Journal Vol Issue Date Pages Journal Short Title
Molecular medicine reports 2 3 2009 May-Jun 455-60 Mol Med Rep
URL
Abstract Text Although imatinib has demonstrated a potent effect on advanced gastrointestinal stromal tumors (GISTs) and has improved the survival of GIST patients, with its prolonged use imatinib resistance is becoming an increasing clinical problem. Mechanisms of secondary resistance are still under investigation. Our study aimed to determine the mechanism of acquired resistance to imatinib in GISTs. Using bidirectional PCR DNA sequencing, we sequenced exons 9, 11, 13 and 17 of the KIT gene and exons 12 and 18 of the PDGFRA gene in secondary resistant lesions obtained from 18 GIST patients after treatment with imatinib. Fourteen of 18 cases carried activating mutations in the KIT gene, with a mutation encoding the juxtamembrane domain present in exon 11 in 12 cases, in exon 13 in 1 case, and in exon 9 in 1 case. In 4 of 10 imatinib-resistant patients, an identical novel missense mutation (T2467G) was found in exon 17, resulting in a substitution of tyrosine by aspartic acid at codon 823 (Y823D). In conclusion, the exon 17 missense mutation T2467G in the tyrosine kinase domain of the KIT gene is correlated with imatinib resistance.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT G565_P573del KIT Y823D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT Y823D was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT G565_P573del mutation who developed resistance to Gleevec (imatinib) (PMID: 21475850). 21475850
KIT V559D KIT Y823D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT Y823D was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT V559D mutation who developed resistance to Gleevec (imatinib) (PMID: 21475850). 21475850
KIT P551_Q556del KIT Y823D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT Y823D was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT P551_Q556del mutation who developed resistance to Gleevec (imatinib) (PMID: 21475850). 21475850