Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell Death Dis. 2017 Oct 12;8(10):e3095. doi: 10.1038/cddis.2017.411.
Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.
尽管索拉非尼目前被用作晚期肝细胞癌的标准治疗方法，但低反应率、短暂和有限的疗效、原发性和获得性耐药以及负面副作用引起了越来越多的关注，这表明需要更好的有效联合治疗。在这里，我们证明索拉非尼诱导或缺氧诱导的缺氧诱导因子（HIF）-2α可以与雄激素受体（AR）启动子 500bp 区域内的缺氧反应元件结合，从而转录抑制 AR。重要的是，体外和体内研究表明，一种特异性和有效的 HIF-2α抑制剂 PT-2385 可以通过抑制 HIF-2α、增加 AR 和抑制下游 pSTAT3/pAKT/pERK 途径来显著增强索拉非尼的疗效。临床样本进一步证实了 HIF-2α和 AR 的作用。令人鼓舞的是，PT-2385 可能通过索拉非尼-PT-2385 联合治疗减轻索拉非尼治疗的不良副作用，这可能为晚期 HCC 患者带来希望。
