Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib

Elena Conca, Claudia Miranda, Valentina Dal Col, Elena Fumagalli, Giuseppe Pelosi, Mara Mazzoni, Maurizio Fermeglia, Erik Laurini, Marco A. Pierotti, Silvana Pilotti, Angela Greco, Sabrina Pricl, Elena Tamborini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)756-762
Number of pages7
JournalMolecular Oncology
Volume7
Issue number4
DOIs
Publication statusPublished - Aug 2013

Keywords

  • Free energy of binding
  • Functional analysis
  • GIST
  • Imatinib
  • KIT mutations
  • Molecular modeling

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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