Reference Detail

Ref Type Journal Article
PMID (16954519)
Authors Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, Eisenberg BL, von Mehren M, Fletcher CD, Sandau K, McDougall K, Ou WB, Chen CJ, Fletcher JA
Title Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 24
Issue 29
Date 2006 Oct 10
Abstract Text Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.


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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
D820A missense unknown KIT D820A lies within the protein kinase domain of the Kit protein ( D820A has been demonstrated to occur as a secondary drug resistance mutation in Kit (PMID: 16954519), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Mar 2019). Y
V560D missense gain of function KIT V560D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 19164557). V560D confers a gain of function on Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT D820A KIT V560D gastrointestinal stromal tumor resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT D820A was identified as a secondary mutation in a patient with gastrointestinal stromal tumor harboring a primary KIT V560D mutation, who developed resistance to Gleevec (imatinib mesylate) (PMID: 16954519). 16954519
KIT D820A KIT V560D gastrointestinal stromal tumor resistant Imatinib Preclinical Actionable In a preclinical study, a gastrointestinal stromal tumor cell line harboring KIT V560D and KIT D820A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 16954519). 16954519