Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents.

However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies.

Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology.

We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.

直到1990年代，细胞毒性化学疗法一直是胃肠道（GI）癌症药物治疗的基石。对癌细胞分子生物学的更好理解导致了靶向疗法的治疗革命，即针对针对在癌细胞中过度表达或突变的蛋白质的单克隆抗体或小分子抑制剂。这些试剂对癌细胞更具特异性，预计其毒性要低于常规细胞毒性试剂。

然而，由于内在的或获得性的耐药机制，或者由于某些肿瘤的局限性，它们的作用有时令人失望，这说明了患者选择和对这些疗法的反应性预测性生物标志物的早期鉴定的重要性。

靶向药物已经在许多胃肠道癌症类型中提供了临床益处。特别是，一些胃肠道肿瘤被认为具有化学抗性，靶向治疗为它们的治疗提供了新的治疗基础。因此，以生长抑素受体为导向的策略，索拉非尼和伊马替尼分别改变了神经内分泌肿瘤（NET），肝细胞癌（HCC）和胃肠道间质瘤（GIST）的治疗方法，目前已被许多人用作一线治疗受这些肿瘤影响的患者。然而，这些试剂面临抗性和从成像和/或生物学鉴定预测性生物标志物的问题。

我们提出了一个由两部分组成的全面综述，为胃肠道肿瘤中靶向药物的成功与失败提供了一种全景方法，以揭示这些药物在胃肠道肿瘤学中的药理学机会和未来方向。在第二部分中，我们将重点介绍NET，HCC和GIST，其治疗主要依赖于靶向疗法。