Abstract
Abstract As part of our previous studies on the anti-tumor mechanisms of sorafenib, one of the primary treatments for advanced hepatocellular carcinoma (HCC), we found that suppression of cyclin E1 in HCC cells correlates with sensitivity to sorafenib (Chiun Hsu et al. Clin Cancer Res. 2016:2555). Furthermore, the combination of sorafenib and a cyclin-dependent kinase inhibitor was found to have synergistic anti-tumor effects. Specifically, we found that inhibiting DKK1 (dickkopf1), an essential regulator of Wnt signaling, had a synergistic effect. In sorafenib-sensitive HCC cells, DKK1 mRNA and protein expressions were suppressed following treatment with sorafenib, but not in sorafenib-resistant cells. HCC cells resistant to sorafenib were induced to apoptosis with knockdown of DKK1 expression. The apoptosis-inducing effects of sorafenib were enhanced by DKK1 inhibitors, and beta-catenin suppression was found to be crucial to this effect. In addition, mouse tumors secrete DKK1 into the blood and its presence correlates positively with tumor size and survival during sorafenib treatment. Suppression of DKK1 in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib or CDK inhibitor efficacy. Sorafenib combined with a DKK1 inhibitor may improve sorafenib's efficacy in hepatocellular carcinoma. (Supported by MOST 106-2314-B-002-229-MY3, MOST 109-2634-F-002-043, MOST 109-2314-B-002-229 -MY3, MOST 110-2634-F-002-044 from Ministry of Science and Technology, Taiwan) Citation Format: Lin Li, Chia-Lang Hsu, Liang-In Lin, Bin-Shyun Lee, Ping-Yun Ou, Ann-Lii Cheng, Chiun Hsu, Da-Liang Ou. DKK1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through beta-catenin suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 376.
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