title: Activate and resist: L576P-KIT in GIST.
abstract: L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated, and shows poor imatinib sensitivity. In this work, histological, immunohistochemical, and biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Delta559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, and KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Delta559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level.
authors.affiliation: Laboratory of Experimental Molecular Pathology, Departments of Pathology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy. sabrina.pricl@dicamp.units.it
authors.forename: Elena
authors.initials: E
authors.lastname: Conca
authors.forename: Tiziana
authors.initials: T
authors.lastname: Negri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.forename: Giovanni Maria
authors.initials: GM
authors.lastname: Pavan
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf