When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.

当胃肠道间质瘤 (GIST) 这种最常见的肉瘤形式在 1990 年代首次被认为是一种独特的病理实体时，由于缺乏有效的药物治疗，晚期疾病患者的预后非常差。KIT的发现突变作为 GIST 的第一个也是最普遍的驱动因素以及随后开发的第一个 KIT 酪氨酸激酶抑制剂 (TKI) 伊马替尼彻底改变了患有这种疾病的患者的治疗。我们现在可以通过分子诊断测试识别 99% 的 GIST 患者的驱动突变，并且已经开发出治疗许多但不是所有疾病分子亚型的疗法。目前，FDA批准用于治疗晚期GIST的药物有7种（imatinib、sunitinib、regorafenib、ripretinib、avapritinib、larotrectinib和entrectinib），均为TKI。尽管这些药物对治疗某些 GIST 亚型非常有效，但挑战依然存在，需要新的治疗方法。在这篇综述中，我们讨论了 GIST 的分子亚型和当前治疗的演变，以及它们的治疗局限性。我们还强调了可能通过基于不同 GIST 分子亚型生物学特征的新策略克服临床挑战的新兴治疗方法。