肝细胞癌仑伐替尼耐药的分子机制

姚晓萌; 孙可可; 林云凯; 汪慧; 董立巍; 陈磊; 胡和平

doi:10.12449/JCH241225

肝细胞癌仑伐替尼耐药的分子机制

DOI: 10.12449/JCH241225

a.
海军军医大学第三附属医院肝胆内科，上海 200438
b.
海军军医大学第三附属医院国家肝癌科学中心，上海 200438

基金项目:

国家重大科学仪器设备开发专项 (2012YQ220113)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：姚晓萌、孙可可负责查阅论文资料，设计论文框架，撰写论文；林云凯、汪慧负责拟定写作思路，修改论文；董立巍、陈磊、胡和平负责指导撰写文章并最后定稿。

详细信息

通信作者:
胡和平， huehbh@126.com （ORCID： 0009-0000-5400-4136）

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出版历程
- 收稿日期: 2024-03-04
- 录用日期: 2024-05-09
- 出版日期: 2024-12-25

Molecular mechanism of lenvatinib resistance in hepatocellular carcinoma

a.
Department of Hepatobiliary Diseases, The Third Affiliated Hospital of Navy Medical University，Shanghai 200438，China
b.
National Center for Liver Cancer, The Third Affiliated Hospital of Navy Medical University，Shanghai 200438，China

Research funding:

National Major Scientific Instrument and Equipment Development Project (2012YQ220113)

摘要

摘要: 肝细胞癌是肝脏最常见的恶性肿瘤，给中国乃至全球带来了严重的卫生负担。然而，大部分肝细胞癌患者就诊时已处于晚期阶段，手术机会较少，治疗选择有限。近年来，分子靶向治疗的进展为晚期肝细胞癌患者提供了新的希望。其中，仑伐替尼是美国食品药品监督管理局继索拉非尼之后批准的第二个用于晚期肝细胞癌治疗的一线药物，因其强大的抗肿瘤特性获得广泛关注。然而，仑伐替尼的疗效受到其耐药性的严重限制。本文主要针对仑伐替尼在肝细胞癌中耐药的分子机制研究进展进行综述，讨论可能改善仑伐替尼耐药的方法，以期能提高其疗效。
- 癌，肝细胞 /
- 仑伐替尼 /
- 抗药性，肿瘤
Abstract: Hepatocellular carcinoma is the most common malignancy of the liver and poses serious health burdens on China and the whole world. However， most patients with hepatocellular carcinoma are already in the advanced stage at the time of diagnosis， with fewer opportunities for surgery and limited treatment options. In recent years， the advances in molecular targeted therapies have brought new hope for patients with advanced hepatocellular carcinoma. Among these therapies， lenvatinib is the second first-line drug after sorafenib approved by the US Food and Drug Administration for the treatment of advanced hepatocellular carcinoma， and it has attracted widespread attention for its powerful anti-tumor properties. However， the efficacy of lenvatinib is severely limited by its drug resistance. This article reviews the research advances in the molecular mechanisms of lenvatinib resistance in hepatocellular carcinoma and discusses possible ways to improve the efficacy of lenvatinib， so as to improve its efficacy.
- Carcinoma， Hepatocellular /
- Lenvatinib /
- Drug Resistance， Neoplasm

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图 1 仑伐替尼部分耐药信号通路

Figure 1. Partial drug resistance signaling pathway for Lenvatinib

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表 1 仑伐替尼耐药机制

Table 1. Lenvatinib resistance mechanism

耐药通路	耐药靶点	耐药模型细胞系	具体耐药机制	逆转耐药策略
EGFR	EGFR	SNU449	EGFR-PAK2-ERK1/2； EGFR-PAK2-ERK5^［6］	联用吉非替尼；联用厄洛替尼
VEGFR2	VEGFR2	Huh7； HepG2	VEGFR2-RAS-MEK-ERK^［10］
FGFR	FGFR1	Hep3B； HepG2	FGFR1-AKT-mTOR； FGFR1-ERK^［12］	氧化槐果碱
MDR1/BCRP 转运体	MDR1/BCRP 转运体	Huh7	促进仑伐替尼外排^［16］	联用依克立达
自噬	LAPTM5	Huh7；HCC-LM3； SNU449	LAPTM5-自噬体-溶酶体融合- 自噬溶酶体形成-耐药^［20］	联用羟氯喹
Wnt/β-catenin 信号通路	IRF2；FZD10；CDK6	HepG2；Huh7；SNU398；Hep3B；PLC/PRF/5	IRF2-β-catenin-抑制凋亡^［25］； FZD10-β-catenin-c-Jun-MEK-ERK^［26］； CDK6-GSK3β-Wnt/β-catenin^［27］	联用帕博西尼
Notch 信号通路	YTHDF1；TM4SF1	Huh7；MHCC97H；LM3；Hep3B；类器官	YTHDF1-m6A-NOTCH1^［30］； TM4SF1-MYH9-NOTCH^［32］	联用DAPT
MAPK/ERK 信号通路	DUSP4；NF1	Huh7；HepG2； PLC/PRF/5	DUSP4缺陷-MAPK/ERK^［34］； NF1缺失-MAPK/ERK^［36］	联用司美替尼；联用曲美替尼
c-Met	miR-128-3p	SMMC-7721； MHCC97-L；Huh7	miR-128-3p-c-Met-EMT^［39］	联用c-MET抑制剂PHA-665752
铁死亡	Nrf2	Huh7；Hep3B	Nrf2-脂质ROS低水平-抑制铁死亡^［41］
ncRNA	lncRNA XIST； lncRNA AC026401.3；lncRNA MT1JP；circMED27	HepG2；MHCC97-L； SMMC-7721；Huh7； PLC/PRF/5；HCCLM3	lncRNA XIST-EZH2-NOD2-ERK^［42］； lncRNA AC026401.3-OCT1-E2F2^［43］； lncRNA MT1JP-miR-24-3p-BCL2L2^［44］； circRNA circMED27-miR-655-3p-USP28^［45］；

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