Tornillo L, Terracciano L M
Institute of Pathology, University of Basel, Basel, Switzerland.
J Clin Pathol. 2006 Jun;59(6):557-63. doi: 10.1136/jcp.2005.031112.
Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal tumours of the gastrointestinal tract. Most of them show activating mutations of the genes coding for KIT or platelet-derived growth factor receptor alpha (PDGFRalpha), two receptor tyrosine kinases (RTKs). The RTK inhibitor Imatinib (Gleevec, Novartis, Switzerland), induces regression of the tumour. The level of response to treatment, together with other clinicopathological parameters is related to the type and site of the activating mutation, thus suggesting that these tumours should be classified according to the molecular context. This is confirmed also by the phenomenon of the resistance to treatment, which arises because of different mechanisms (second mutation, amplification, activation of other RTKs) and can be fought only by specific RTK inhibitors, that are at present under development. RTK activation involves an homogeneous transduction pathway whose components (MAPK, AKT, PI3K, mTOR and RAS) are possible targets of new molecular treatment. A new paradigm of classification integrating the classic pathological criteria with the molecular changes will permit personalised prognosis and treatment.
胃肠道间质瘤（GISTs）是胃肠道最常见的原发性间充质肿瘤。其中大多数表现为编码KIT或血小板衍生生长因子受体α（PDGFRα）的基因激活突变，这两种都是受体酪氨酸激酶（RTK）。RTK抑制剂伊马替尼（格列卫，诺华公司，瑞士）可诱导肿瘤消退。治疗反应水平以及其他临床病理参数与激活突变的类型和部位有关，因此提示这些肿瘤应根据分子背景进行分类。治疗耐药现象也证实了这一点，耐药是由不同机制（二次突变、扩增、其他RTK激活）引起的，目前只能通过正在研发的特定RTK抑制剂来对抗。RTK激活涉及一条同源转导途径，其组成部分（MAPK、AKT、PI3K、mTOR和RAS）可能是新分子治疗的靶点。将经典病理标准与分子变化相结合的新分类模式将实现个性化预后和治疗。
