Department of Oncology, Cancer Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
Cancer Res. 2023 Jan 4;83(1):89-102. doi: 10.1158/0008-5472.CAN-22-0963.
The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (m7G) methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.
Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.
酪氨酸激酶抑制剂仑伐替尼是治疗晚期肝细胞癌（HCC）患者的一线药物。然而，其疗效受到耐药性的严重阻碍。深入了解仑伐替尼耐药的分子机制可以提供新的策略来改善和延长反应。在这里，我们对亲本和仑伐替尼耐药 HCC 细胞进行了无偏置蛋白质组筛选，发现甲基转移酶样蛋白 1（METTL1）和 WD 重复结构域 4 蛋白（WDR4），即 tRNA N7-甲基鸟苷（m7G）甲基转移酶复合物的两个关键组成部分，在仑伐替尼耐药细胞中显著上调。METTL1 敲低通过损害 HCC 细胞的增殖能力并在仑伐替尼治疗下促进细胞凋亡来克服耐药性。此外，野生型 METTL1 的过表达而非其催化失活突变可诱导仑伐替尼耐药。包括水力注射、皮下植入和原位异种移植小鼠模型在内的动物实验进一步证明了 METTL1/WDR4 介导的 m7G tRNA 修饰在体内促进仑伐替尼耐药中的关键作用。从机制上讲，METTL1 促进 EGFR 通路基因的翻译以引发耐药性。这项工作揭示了 METTL1 介导的 m7G tRNA 修饰在促进仑伐替尼耐药中的重要作用，并为耐药性提供了有前途的预测标志物和干预靶点。
tRNA m7G 甲基转移酶复合物成分 METTL1 和 WDR4 的上调促进了 HCC 中的仑伐替尼耐药性，并赋予了对 METTL1 靶向的敏感性，为克服耐药性提供了有前途的策略。
