National Institute of Cancer Research, National Health Research Institutes, No.367, Sheng-Li Rd., North Dist., 70456, Tainan, Taiwan.
Curr Treat Options Oncol. 2019 Feb 18;20(3):22. doi: 10.1007/s11864-019-0622-9.
Melanoma is the deadliest form of skin cancer worldwide. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to identify more effective therapeutic targets. Approximately, one half of advanced melanoma bears a mutation in the BRAF gene that makes BRAF as an important therapeutic target. Significant clinical benefit is associated with BRAF and MEK inhibitors (MAPKi) on targeting patients with BRAF V600 mutations. However, the frequent and rapid development of acquired resistance still is the major challenge facing the melanoma. Several mechanisms by which melanoma passes the inhibitory effects of MAPKi have been characterized and clinically translated, but additional alternations of genetic and epigenetic regulators outside of MAPK and/or AKT networks occurs in a quarter of patients with acquired MAPKi resistance. These studies implicate that targeting signaling networks external MAPK or AKT pathways is critical. In this review, we will focus on two approaches that are under evaluating for targeting melanoma: (1) against genome instability by p53 network restoration and (2) disrupt cancer proteome by chaperone inhibition.
黑色素瘤是全球致死率最高的皮肤癌。黑色素瘤发病率和死亡率不断上升，且极易转移，这凸显出寻找更有效治疗靶点的紧迫性。大约一半的晚期黑色素瘤患者的 BRAF 基因发生突变，使 BRAF 成为一个重要的治疗靶点。针对携带 BRAF V600 突变的患者，BRAF 和 MEK 抑制剂（MAPKi）可显著提高临床获益。然而，获得性耐药的频繁和快速发展仍然是黑色素瘤面临的主要挑战。已经有几种机制被证实可以使黑色素瘤逃避 MAPKi 的抑制作用，并在临床上得到了转化，但在四分之一的获得性 MAPKi 耐药患者中，除了 MAPK 和/或 AKT 网络之外，还存在其他遗传和表观遗传调节因子的改变。这些研究表明，靶向 MAPK 或 AKT 通路以外的信号转导网络至关重要。在这篇综述中，我们将重点介绍两种正在评估用于治疗黑色素瘤的方法：（1）通过 p53 网络恢复来对抗基因组不稳定性，（2）通过伴侣蛋白抑制来破坏癌症蛋白质组。
