Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, China.
Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, China.
Aging (Albany NY). 2020 Nov 16;12(22):22975-23003. doi: 10.18632/aging.104028.
For nearly a decade, sorafenib has served as a first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma (HCC), but it displays only limited efficacy against advanced drug-resistant HCC. Regorafenib, the first second-line drug approved for treatment after sorafenib failure, can reverse resistance to sorafenib. We used bioinformatics methods to identify genes whose expression was differentially induced by sorafenib and regorafenib in HCC. We identified as an oncogene involved in the acquired resistance to sorafenib in HCC and investigated its potential as a target for reversing this resistance. Sustained exposure of resistant HCC cells to sorafenib activated the AKT pathway, which in turn upregulated KIF14 expression by increasing expression of the transcription factor ETS1. Silencing reversed the acquired resistance to sorafenib by inhibiting AKT activation and downregulating ETS1 expression by blocking the AKT-ETS1-KIF14 positive feedback loop. Moreover, injection of with sorafenib suppressed growth of sorafenib-resistant HCC tumors in mice. These results demonstrate that targeting KIF14 could be an effective means of reversing sorafenib failure or strengthening sorafenib's antitumor effects.
近十年来，索拉非尼一直是治疗肝细胞癌（HCC）的一线化疗药物，但对晚期耐药 HCC 的疗效有限。regorafenib 是索拉非尼治疗失败后的第一种二线药物，可逆转索拉非尼耐药。我们使用生物信息学方法鉴定了 sorafenib 和 regorafenib 在 HCC 中差异诱导表达的基因。我们鉴定了 作为 HCC 中对索拉非尼获得性耐药的致癌基因，并研究了其作为逆转这种耐药性的靶标的潜力。耐药 HCC 细胞持续暴露于 sorafenib 激活了 AKT 通路，通过增加转录因子 ETS1 的表达，从而上调 KIF14 的表达。沉默 通过抑制 AKT 激活和下调 ETS1 表达，阻断 AKT-ETS1-KIF14 正反馈环，逆转了对 sorafenib 的获得性耐药。此外，用 sorafenib 注射 抑制了小鼠中 sorafenib 耐药 HCC 肿瘤的生长。这些结果表明，靶向 KIF14 可能是逆转 sorafenib 失败或增强 sorafenib 抗肿瘤作用的有效手段。
