title: Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.
abstract: Gastrointestinal stromal tumors carry in about 85% of the cases activating mutations in KIT gene. Generally only one KIT mutation is found in primary tumors and the majority of mutations affecting KIT exon 11 is sensitive to Imatinib. We report upon a GIST case harboring a double-mutant KIT gene at exon 11, which expresses a receptor bearing the known activating W557G mutation and a newly discovered missense Y578C alteration. The relative affinities for ATP and Imatinib of each single (W557G, Y578C) and double (W557G/Y578C) mutant KITs were predicted by in silico studies (computer-based molecular simulations), and compared with those obtained for known Imatinib sensitive and resistant KIT mutants. In parallel, biochemical analysis of the single and double KIT mutants expressed in mammalian cells was performed. Both the in-silico/in-vitro investigations showed constitutive activation and sensitivity to Imatinib of the yet mentioned Y578C mutation as well as of the double mutant, providing evidence that the concomitant presence of the W557G and Y578C mutations does not affect Imatinib response compare to the single mutations, in line with what observed in Imatinib treated patient.
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Conca
authors.forename: Claudia
authors.initials: C
authors.lastname: Miranda
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Col
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Mara
authors.initials: M
authors.lastname: Mazzoni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
mesh_terms: D000368:Aged; D001549:Benzamides / Q000627:therapeutic use*; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
keywords: Free energy of binding; Functional analysis; GIST; Imatinib; KIT mutations; Molecular modeling