Treatment options for advanced hepatocellular carcinoma (HCC) are limited. Although some multikinase inhibitors such as sorafenib show some benefit, this does not significantly alter the course of disease for most patients. Currently, several multikinase inhibitors were shown to work in first-line or second-line treatments, but the overall benefit is quite small. Thus, we urgently need to find ways to increase response rates and perhaps more important, to be able to sustain responses for longer periods.1 Chemotherapy combinations changed the history of cancer therapy when first introduced in childhood malignancies and such combinations remain the main treatment option for many cancer patients. Some kinase inhibitors were also shown to work better in combination—for example, the combination of B-RAF and MEK inhibitors in advanced melanoma showed significantly improved rates of progression-free and overall survival versus B-RAF inhibition alone.2 The choice of the combination in this case was made based on preclinical data suggesting that MEK activation is a major determinant of progression in vemurafenib (a B-RAF-inhibitor) treated melanomas. In the absence of clear cut mechanisms of acquired resistance to sorafenib (which is a multikinase inhibitor), how can we find drug combinations which will increase its efficacy? One way to search for therapeutic targets is the loss of function …

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我们准备好接受 HCC 的靶向治疗组合了吗？

晚期肝细胞癌 (HCC) 的治疗选择是有限的。尽管一些多激酶抑制剂如索拉非尼显示出一些益处，但这并没有显着改变大多数患者的病程。目前，几种多激酶抑制剂已被证明可用于一线或二线治疗，但总体收益很小。因此，我们迫切需要找到提高反应率的方法，也许更重要的是，能够维持更长时间的反应。 1 化疗组合在儿童恶性肿瘤首次引入时改变了癌症治疗的历史，这种组合仍然是主要的治疗选择对于许多癌症患者。一些激酶抑制剂也被证明可以更好地组合使用——例如，在晚期黑色素瘤中，B-RAF 和 MEK 抑制剂的组合与单独使用 B-RAF 抑制剂相比显示出显着提高的无进展和总生存率。2 在这种情况下选择组合是基于临床前数据表明 MEK 激活是vemurafenib（一种 B-RAF 抑制剂）治疗的黑色素瘤进展的主要决定因素。在对索拉非尼（一种多激酶抑制剂）的获得性耐药性缺乏明确机制的情况下，我们如何才能找到能提高其疗效的药物组合？寻找治疗靶点的一种方法是功能丧失…… 2 在这种情况下，组合的选择是基于临床前数据做出的，这些数据表明 MEK 激活是 vemurafenib（一种 B-RAF 抑制剂）治疗的黑色素瘤进展的主要决定因素。在对索拉非尼（一种多激酶抑制剂）的获得性耐药性缺乏明确机制的情况下，我们如何才能找到能提高其疗效的药物组合？寻找治疗靶点的一种方法是功能丧失…… 2 在这种情况下，组合的选择是基于临床前数据做出的，这些数据表明 MEK 激活是 vemurafenib（一种 B-RAF 抑制剂）治疗的黑色素瘤进展的主要决定因素。在对索拉非尼（一种多激酶抑制剂）的获得性耐药性缺乏明确机制的情况下，我们如何才能找到能提高其疗效的药物组合？寻找治疗靶点的一种方法是功能丧失……