title: Acquired resistance to imatinib and secondary KIT exon 13 mutation in gastrointestinal stromal tumour.
abstract: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Most of them have an activating mutation of KIT or PDGFRalpha tyrosine-kinase receptors. Imatinib is a selective tyrosine-kinase inhibitor of ABL, KIT and PDGFR, and provides a clinical benefit in about 85% of patients with advanced GIST. Unfortunately, secondary resistance following initial responses occurs in most of the cases, and molecular mechanisms are poorly understood. We sequenced KIT and PGDFRalpha exons from one patient with GIST before and after the development of imatinib resistance. We identified, in addition to a primary mutation in exon 9, a secondary mutation in KIT exon 13 (first kinase domain) in the resistant sample. We demonstrate for the first time the feasibility of sequencing such samples removed by non-surgical biopsies during imatinib therapy. Such a approach, far less invasive than surgery and combined with sequencing, will likely help in better tailoring the treatment of advanced GISTs and understanding the mechanisms of resistance and response to imatinib.
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli-Calmettes, 13009 Marseille, France. bertuccif@marseille.fnclcc.fr
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Anthony
authors.initials: A
authors.lastname: Goncalves
authors.forename: Geneviève
authors.initials: G
authors.lastname: Monges
authors.forename: Anne
authors.initials: A
authors.lastname: Madroszyk
authors.forename: Jérome
authors.initials: J
authors.lastname: Guiramand
authors.forename: Vincent
authors.initials: V
authors.lastname: Moutardier
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Noguchi
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Hagay
authors.initials: H
authors.lastname: Sobol
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001706:Biopsy; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D017422:Sequence Analysis, DNA; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta