CT-707 通过抑制 YAP 信号通路克服肝癌中缺氧介导的索拉非尼耐药性。
CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling.
机构信息
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, USA.
出版信息
BMC Cancer. 2022 Apr 19;22(1):425. doi: 10.1186/s12885-022-09520-5.
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome.
MATERIALS AND METHODS
The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia.
RESULTS
Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC.
CONCLUSIONS
Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.
背景
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。索拉非尼是晚期 HCC 的一线治疗药物，但由于其反应率低且无法延长无进展生存期（PFS），其抗癌效果仍有待提高。因此，迫切需要探索改善临床疗效的方法。
材料和方法
分别在常氧和缺氧条件下通过 SRB（磺基罗丹明 B）测定法分析索拉非尼对 HCC 的作用。通过 SRB 测定法分析 CT707 与索拉非尼在缺氧条件下的不同剂量组合效应。用 CT707 和索拉非尼处理缺氧时的流式细胞术检测细胞凋亡率。用 Western blot 检测凋亡相关蛋白的表达水平及 CT707 克服缺氧中索拉非尼耐药的机制。
结果
本研究表明，晚期 HCC 的肿瘤内缺氧特征是介导 HCC 中索拉非尼耐药的主要因素之一。新型多激酶抑制剂 CT-707 可使缺氧 HCC 细胞对索拉非尼敏感。进一步的研究表明，CT-707 可消除 Yes 相关蛋白（YAP）的核转位，YAP 已被证明是 HCC 中缺氧介导的索拉非尼耐药的机制之一。
结论
总的来说，这项研究不仅有利于开发新型多激酶抑制剂 CT-707 作为治疗 HCC 的药物，而且为克服 HCC 患者缺氧介导的对索拉非尼的耐药性提供了一种潜在策略。
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