Chen Ronggao, Hu Xin, Huang Yingchen, Jiang Yao, Chen Guanrong, Shan Qiaonan, Xu Xiao, Zheng Shusen
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China.
Int J Biol Sci. 2025 Feb 18;21(5):2012-2026. doi: 10.7150/ijbs.107195. eCollection 2025.
Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), has been established as the first-line treatment for advanced hepatocellular carcinoma (HCC) because of its superior efficacy when in comparison with sorafenib. However, the inevitable development of drug resistance is a significant barrier to achieve a curative outcome and negatively impacts the prognosis. Therefore, it is imperative to delve into the mechanisms underlying lenvatinib resistance (LR) and to identify potential strategies for rational combination treatments. Regulated cell death (RCD) refers to the process by which cells undergo demise when the adaptive responses are insufficient to maintain homeostasis, and RCD takes a crucial part in the disease progression and response to therapeutic agents including TKI of cancer. Resisting cell death is one of the fundamental hallmarks and the major reasons contributing to drug resistance in cancer. Particularly, numerous studies have demonstrated that RCD (including apoptosis, autophagy, ferroptosis, cuproptosis and pyroptosis) plays a significant role in the emergence of LR in HCC. This article offers an in-depth review of recent discoveries concerning the mechanisms of LR in relation to RCD and proposes potential strategies to boost the effectiveness of lenvatinib by incorporating RCD modulators.
仑伐替尼是一种多靶点酪氨酸激酶抑制剂（TKI），由于其与索拉非尼相比具有更优的疗效，已被确立为晚期肝细胞癌（HCC）的一线治疗药物。然而，不可避免的耐药性发展是实现治愈性结果的重大障碍，并对预后产生负面影响。因此，深入探究仑伐替尼耐药（LR）的潜在机制并确定合理联合治疗的潜在策略势在必行。调节性细胞死亡（RCD）是指当适应性反应不足以维持体内平衡时细胞发生死亡的过程，RCD在疾病进展以及对包括癌症TKI在内的治疗药物的反应中起关键作用。抵抗细胞死亡是癌症耐药的基本特征之一，也是导致癌症耐药的主要原因。特别是，大量研究表明，RCD（包括凋亡、自噬、铁死亡、铜死亡和焦亡）在HCC的LR发生中起重要作用。本文深入综述了近期关于LR与RCD相关机制的发现，并提出了通过纳入RCD调节剂来提高仑伐替尼疗效的潜在策略。
