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LXRα激活和Raf抑制可引发肝癌致死性脂肪毒性

原文发布日期：2021-02-15

英文摘要：

摘要翻译：

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文章：

LXRα激活和Raf抑制可引发肝癌致死性脂肪毒性

LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer

原文发布日期：2021-02-15

英文摘要：

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer.

摘要翻译：

在癌症治疗中靶特定代谢途径的分子疗法的成功往往受限于代谢网络的多变性和适应性。在这里，我们显示了药物诱导的脂毒性作为一种有潜力的治疗方法，可用于治疗肝细胞癌（HCC）。LXRα诱导的脂生成和Raf-1抑制因饱和脂肪酸的有毒积累在HCC中具有组合致死性。Raf-1被发现与SCD1结合并激活其活性，并且DFG-out Raf抑制剂可以通过改变构象来干扰这一相互作用，从而阻止脂肪酸脱氢作用导致有毒的脂毒性。在基因工程型肝癌和非酒精性脂肪性肝癌（NASH）诱导的HCC小鼠模型以及人类HCC的人体异物模型中开展的研究表明，包含LXR激动剂和Raf抑制剂的疗法耐受良好且能够克服HCC的治疗抗性。概念上来说，我们的研究提示药物诱导的脂毒性作为一种新的肝脏癌代谢靶向的方法。