Chen Anling, Yin Ke, Liu Yu, Hu Lei, Cui Qianwen, Wan Xiaofeng, Yang Wulin
Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
Science Island Branch, Graduate School of University of Science and Technology of China, Hefei, 230031, China.
Curr Cancer Drug Targets. 2025;25(4):370-385. doi: 10.2174/0115680096298370240520093003.
Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited.
This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib.
We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation.
We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1.
Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.
索拉非尼是目前晚期肝细胞癌患者的治疗首选，但疗效仍有限。
本研究旨在探讨WEE家族激酶抑制剂是否能增强索拉非尼的抗癌效果。
我们分析了肝细胞癌中PKMYT1激酶和WEE1激酶的表达水平，研究了PKMYT1激酶抑制剂RP - 6306、WEE1激酶抑制剂阿瓦斯丁与索拉非尼联合对肝癌细胞增殖的抑制作用，并检测了药物联合对CDK1磷酸化的影响。
我们发现PKMYT1和WEE1在肝细胞癌中上调，对患者生存不利。细胞实验表明，RP - 6306和阿瓦斯丁（1 - 100 μM）单独使用时均以剂量依赖方式抑制肝癌细胞系的增殖，两种药物联合具有协同作用。在肝癌细胞系中，索拉非尼与RP - 6306或阿瓦斯丁联合显示出协同抗增殖作用，对正常细胞毒性较小。索拉非尼与RP - 6306和阿瓦斯丁联合进一步抑制肝癌细胞增殖，并导致CDK1完全去磷酸化。
综上所述，我们的研究结果为索拉非尼未来联合RP - 6306或阿瓦斯丁治疗肝细胞癌提供了实验证据。
