Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.

中文翻译：

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药物基因组学数据的总结表明，SULF2的无效增强了索拉非尼在肝癌中的易感性。

基因突变在癌症的发展和进程中起着至关重要的作用，因此代表着精准医学的目标。在这里，我们概述了药物基因组学数据，以描述可操作的突变和治疗靶标药物的新型候选药物。作为概念验证，我们证明了突变（N491K）或抑制引起的SULF2功能丧失增强了肝癌细胞和体内小鼠模型中的索拉非尼敏感性。该作用是通过EGFR信号传导的失调和LCN2的下游表达来介导的。我们还报告说，对索拉非尼治疗无反应的肝癌患者表现出较高的SULF2和LCN2表达。总之，我们认为SULF2通过放松LCN2在肝癌中对索拉非尼的敏感性和耐药性中起关键作用。