Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China.
School of Pharmacy, Guangdong Medical University, Zhanjiang, China.
Liver Int. 2024 Aug;44(8):1808-1831. doi: 10.1111/liv.15953. Epub 2024 May 3.
Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer-related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib for first-line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano-delivery carriers may be possible approaches.
肝细胞癌 (HCC) 是全球最常见和最具破坏性的癌症相关死亡原因之一，大约 70%的 HCC 患者在诊断时已处于晚期疾病，限制了根治性治疗的可能性。对于这些患者来说，乐伐替尼是索拉非尼的一种期待已久的一线靶向治疗替代药物，已成为关键治疗方法。不幸的是，尽管取得了一些进展，但由于耐药性的发展，晚期 HCC 的预后仍然很差。然而，导致 HCC 对乐伐替尼耐药的分子机制以及缓解 HCC 耐药性的方法在很大程度上尚不清楚且缺乏系统总结；因此，本综述不仅旨在探讨导致 HCC 对乐伐替尼耐药的因素，更重要的是，总结克服或减轻耐药性的潜在方法。结果表明，异常激活的通路、药物转运、表观遗传学、肿瘤微环境、癌症干细胞、调控性细胞死亡、上皮-间充质转化等机制参与了 HCC 中乐伐替尼耐药的发展以及随后的 HCC 进展。为了提高乐伐替尼的治疗效果，抑制获得性耐药、联合治疗和纳米递药载体可能是可行的方法。
