希佩尔-林道(VHL)综合征以VHL基因突变为疾病的基础起源。VHL突变可以使同一患者一生中诱发多种不同部位的良恶性肿瘤。肾细胞癌是VHL患者重要的临床类型,也是患者死亡的重要原因。包括血管内皮生长因子(VEGF)通路、雷帕霉素靶蛋白(mTOR)通路、缺氧诱导因子-2α(HIF-2α)通路、促红细胞生成素(EPO)通路被证实与其发病息息相关。VHL突变导致的肾癌高度血管化特征是多种靶向药物治疗VHL肾癌的基础,如贝伐单抗、舒尼替尼等药物已经取得不错的疗效。而基于HIF-2α的新药belzutifan以及第3代mTOR受体抑制剂Rapalink-1也为VHL肾癌治疗提供了新的手段。综述了VHL突变与上述通路的致癌机制,并结合相关靶向药物的应用和新药研发进行了阐述,有望为将来的新药研发提供了有益的思考。

Hippel-Lindau (VHL) syndrome has mutations in the VHL gene as the underlying origin of the disease. The mutation can predispose the same patient to multiple benign and malignant tumors at different sites during their lifetime. Renal cell carcinoma is an important clinical type in patients with VHL and an important cause of death. Multiple pathways including VEGF, mTOR, HIF-2α, and EPO have been shown to be involved in its pathogenesis, and the highly vascularised nature of kidney cancer due to VHL mutations is the basis for the treatment of VHL kidney cancer with a variety of targeted drugs. Drugs such as bevacizumab and sunitinib have achieved good efficacy. The new HIF-2α-based drug belzutifan and the third-generation mTOR receptor inhibitor Rapalink-1 also offers new prospects for treatment. This article reviews the oncogenic mechanism of VHL mutations and the above pathways, and expounds the application and new drug development combined with related targeted drugs, which is expected to provide useful food for thought for future new drug development.

R979.1