希佩爾-林道(VHL)綜合征以VHL基因突變?yōu)榧膊〉幕A(chǔ)起源。VHL突變可以使同一患者一生中誘發(fā)多種不同部位的良惡性腫瘤。腎細(xì)胞癌是VHL患者重要的臨床類型,也是患者死亡的重要原因。包括血管內(nèi)皮生長因子(VEGF)通路、雷帕霉素靶蛋白(mTOR)通路、缺氧誘導(dǎo)因子-2α(HIF-2α)通路、促紅細(xì)胞生成素(EPO)通路被證實與其發(fā)病息息相關(guān)。VHL突變導(dǎo)致的腎癌高度血管化特征是多種靶向藥物治療VHL腎癌的基礎(chǔ),如貝伐單抗、舒尼替尼等藥物已經(jīng)取得不錯的療效。而基于HIF-2α的新藥belzutifan以及第3代mTOR受體抑制劑Rapalink-1也為VHL腎癌治療提供了新的手段。綜述了VHL突變與上述通路的致癌機(jī)制,并結(jié)合相關(guān)靶向藥物的應(yīng)用和新藥研發(fā)進(jìn)行了闡述,有望為將來的新藥研發(fā)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