Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA.
Division of Hematology/Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Hepatology. 2024 Apr 1;79(4):926-940. doi: 10.1097/HEP.0000000000000237. Epub 2023 Jan 3.
HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.
HCC 占原发性肝癌的 80%左右。HCC 是唯一一种过去 10 年来死亡率没有改善的主要癌症。大多数患者在手术和局部治疗不可行或无效时被诊断为晚期疾病。索拉非尼是一种针对细胞生长和血管生成的多激酶抑制剂，于 2007 年被批准用于不可切除的晚期 HCC。此后，其他多激酶抑制剂也获得了批准。仑伐替尼被发现作为一线药物与索拉非尼非劣效。regorafenib、cabozantinib 和 ramucirumab 被证明作为二线药物可延长生存期。HCC 的免疫治疗进展也为患者带来了希望，但疗效仍然有限。由于原发性和获得性耐药，很大一部分晚期 HCC 患者无法从系统治疗中获得长期获益，再加上发病率的上升，HCC 仍然是一种高度致命的疾病。这篇综述总结了对治疗的原发性和获得性耐药的机制，并包括了克服耐药的方法。它探讨了免疫治疗的最新进展，为耐药性与 HCC 的分子病因之间的联系提供了新的视角，并评估了微生物组在耐药性中的作用。它还讨论了信号通路的改变、细胞凋亡的失调、肿瘤微环境的调节、癌症干细胞的参与、药物代谢/转运的变化、肿瘤缺氧、DNA 修复以及 microRNAs 在耐药性中的作用。了解这些因素之间的相互作用将为开发能够改善患者预后的新治疗策略提供指导。
