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|Ref Type||Journal Article|
|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||Journal of clinical oncology : official journal of the American Society of Clinical Oncology|
|Date||2003 Dec 01|
|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.|
|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|
|PDGFRA||I843_M844del||deletion||gain of function - predicted||PDGFRA I843_M844del results in the deletion of two amino acids in the protein kinase domain of the Pdgfra protein between amino acids 843 to 844 (UniProt.org). I843_M844del has not been characterized, however, similar PDGFRA exon 18 deletions are activating (PMID: 15928335, PMID: 14645423) and therefore, is predicted to result in a gain of function.|
|PDGFRA||I843del||deletion||gain of function||PDGFRA I843del results in the deletion of one amino acid in the protein kinase domain of the Pdgfra protein (UniProt.org). I843del confers a gain of function on the Pdgfra protein as indicated by increased ligand-independent phosphorylation of Pdgfra in cell culture (PMID: 22745105, PMID: 14645423).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PDGFRA I843del||Advanced Solid Tumor||sensitive||Imatinib||Preclinical||Actionable||In a preclinical study, Gleevec (imatinib) decreased phosphorylation of Pdgfra in cell lines expressing PDGFRA I843del mutation in culture (PMID: 14645423).||14645423|