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Ref Type Journal Article
PMID (14645423)
Authors Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA
Title Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.
Journal Vol Issue Date Pages Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21 23 2003 Dec 01 4342-9 J Clin Oncol
URL
Abstract Text Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome.Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation.Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

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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 V560G Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT V560G in culture (PMID: 14645423). 14645423
KIT exon11 gastrointestinal stromal tumor sensitive Imatinib Phase II Actionable In a Phase II trial, Gleevec (imatinib) treatment in patients with gastrointestinal stromal tumors resulted in a partial response rate of 75.7% (87/115) overall, and led to an increased partial response rate (83.5% vs 47.8%, p=0.0006), event-free survival (687 vs 200 days, p<0.0001), and overall survival (p=0.0034) in patients harboring KIT exon 11 mutations (n=85) compared to patients with KIT exon 9 mutations (n=23) (PMID: 14645423). 14645423
KIT A502_Y503dup Advanced Solid Tumor sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT A502_Y503dup (referred to as Y503_F504insAY) in culture (PMID: 14645423). 14645423
KIT N822K Advanced Solid Tumor conflicting Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT N822K in culture (PMID: 14645423). 14645423
KIT W557_K558del Advanced Solid Tumor sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT W557_K558del in culture (PMID: 14645423). 14645423
KIT N822H Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT N822H in culture (PMID: 14645423). 14645423
KIT K642E Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment decreased Kit autophosphorylation in cells expressing KIT K642E in culture (PMID: 14645423). 14645423