Huang Yilan, Wang Siwei, Zhang Xiaojun, Yang Chen, Wang Sikai, Cheng Hongxia, Ke Aiwu, Gao Chao, Guo Kun
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Shanghai, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education, Shanghai, China; Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
Pharmacol Res. 2024 Feb;200:107082. doi: 10.1016/j.phrs.2024.107082. Epub 2024 Jan 26.
Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.
乐伐替尼是晚期肝细胞癌（HCC）患者的一线酪氨酸激酶抑制剂。然而，只有25%的患者能从该治疗中获益，并且总会出现获得性耐药。迄今为止，既没有有效的药物来对抗乐伐替尼耐药，也没有准确的标志物可以预测患者对乐伐替尼治疗的反应情况。因此，迫切需要识别和应对乐伐替尼耐药的新策略。在当前研究中，首次建立了一个强大的乐伐替尼耐药指数（LRi）模型来预测HCC患者对乐伐替尼的反应状态。随后，通过进行连接性图谱（CMap）分析初步筛选出五种能够逆转乐伐替尼耐药特征的候选药物（巯嘌呤、AACOCF3、NU1025、法舒地尔和依西美坦），最终通过一系列体外细胞功能试验和异种移植小鼠模型，法舒地尔脱颖而出。转录组学研究表明，乐伐替尼与法舒地尔联合使用通过重塑刺猬信号通路克服了乐伐替尼耐药。从机制上讲，乐伐替尼对表皮生长因子受体（EGFR）的反馈激活导致GLI2 - ABCC1通路的激活，从而支持肝癌细胞的存活和增殖。值得注意的是，乐伐替尼与法舒地尔联合使用显著抑制了刺猬信号通路的上游开关IHH，以抵消GLI2的激活，最终增强了乐伐替尼的疗效。这些发现阐明了一种新的EGFR介导的乐伐替尼耐药机制，并通过有意义的药物再利用策略提供了一种克服HCC耐药的实用方法。
