Bertucci François, Goncalves Anthony, Monges Geneviève, Madroszyk Anne, Guiramand Jérome, Moutardier Vincent, Noguchi Tetsuro, Dubreuil Patrice, Sobol Hagay
Département d'Oncologie Médicale, Institut Paoli-Calmettes, 13009 Marseille, France.
Oncol Rep. 2006 Jul;16(1):97-101.
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.
胃肠道间质瘤（GISTs）是胃肠道最常见的间充质肿瘤。其中大多数具有KIT或PDGFRα酪氨酸激酶受体的激活突变。伊马替尼是一种ABL、KIT和PDGFR的选择性酪氨酸激酶抑制剂，约85%的晚期GIST患者使用后可获得临床益处。不幸的是，大多数病例在初始反应后会出现继发性耐药，其分子机制尚不清楚。我们对一名GIST患者在伊马替尼耐药前后的KIT和PGDFRα外显子进行了测序。我们在耐药样本中除了发现外显子9的原发性突变外，还发现了KIT外显子13（第一个激酶结构域）的继发性突变。我们首次证明了在伊马替尼治疗期间对通过非手术活检获取的此类样本进行测序的可行性。这种方法比手术侵入性小得多，并且与测序相结合，可能有助于更好地调整晚期GIST的治疗方案，并了解对伊马替尼的耐药和反应机制。
