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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.
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
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT C809G missense unknown KIT C809G lies within the protein kinase domain of the Kit protein ( C809G has been associated with secondary resistance to select KIT inhibitors (PMID: 16954519), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Mar 2023). Y
KIT D820A missense gain of function - predicted KIT D820A lies within the protein kinase domain of the Kit protein ( D820A has been demonstrated to occur as a secondary drug resistance mutation (PMID: 16954519, PMID: 31363162), and results in reduced Kit protein expression and stability, abnormal cellular localization, but constitutive Kit phosphorylation in the absence of Pkc in cell culture (PMID: 27440273), and therefore, is predicted to lead to a gain of Kit protein function. Y
KIT 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 to Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291, PMID: 27440273) despite reduced expression, enhanced degradation, and cellular mislocalization (PMID: 27440273).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560D KIT D820A 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
KIT K642E KIT C809G KIT N822H gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, an acquired KIT C809G mutation was identified in a gastrointestinal stromal tumor (GIST) patient harboring KIT K642E and KIT N822H at the time of progression on Gleevec (imatinib) (PMID: 16954519). 16954519
KIT C809G Advanced Solid Tumor predicted - resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, KIT C809G was resistant to inhibition of phosphorylation by Gleevec (imatinib) in cultured cells (PMID: 16954519). 16954519
KIT V560D KIT D820A 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