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|Ref Type||Journal Article|
|Authors||Tamborini E, Pricl S, Negri T, Lagonigro MS, Miselli F, Greco A, Gronchi A, Casali PG, Ferrone M, Fermeglia M, Carbone A, Pierotti MA, Pilotti S|
|Title||Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.|
|Date||2006 Oct 5|
|Abstract Text||Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 microM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.|
|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||V654A||missense||unknown||KIT V654A lies within the protein kinase domain (exon 13) of the Kit protein (UniProt.org). V654A has been described as a secondary drug resistance mutation (PMID: 17363509, PMID: 16751810), but has conflicting functional data, as in some studies, results in increased proliferation in cultured cells and in murine cells (corresponding to V653A), leads to increased proliferation and elevated Stat activation in the context of KIT V559del (corresponding to V558del in mouse) in culture (PMID: 33024275), is constitutively phosphorylated in culture (PMID: 27440273), but in another study is not transforming and does not result in constitutive activation (PMID: 17363509), and therefore, its effect on Kit protein function is unknown.||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT V654A||Advanced Solid Tumor||resistant||Imatinib||Preclinical||Actionable||In a preclinical study, cells expressing KIT V654A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 16751810).||16751810|