Yousef Eman H, El Gayar Amal M, El-Magd Nada F Abo
Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Crit Rev Oncol Hematol. 2025 May 17;212:104765. doi: 10.1016/j.critrevonc.2025.104765.
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
最常见的原发性肝癌——肝细胞癌（HCC），预后较差。近几十年来，HCC的患病率和相关死亡人数有所增加。美国食品药品监督管理局（FDA）已批准索拉非尼作为晚期HCC患者的一线治疗药物。尽管如此，一些临床研究表明，相当比例的肝癌患者对索拉非尼不敏感。此外，索拉非尼的总体疗效远远不够，受益于该治疗的患者数量较少。近年来，许多研究人员专注于索拉非尼耐药的潜在机制。据报道，HCC细胞对索拉非尼的获得性耐药与信号转导和转录激活因子3（STAT3）激活失调、血管生成、自噬、缺氧诱导通路、上皮-间质转化（EMT）、癌症干细胞（CSC）、铁死亡和非编码RNA（ncRNA）有关。最近的临床试验，包括索拉非尼与替雷利珠单抗等免疫检查点抑制剂的比较，已显示出改善患者预后的前景。此外，针对互补通路的联合疗法正在研究中，以克服耐药性并提高治疗效果。索拉非尼有效性的局限性已部分但未完全阐明。此外，虽然某些治疗方案已显示出积极结果，但仍需要更多临床试验来证实。未来的研究应专注于确定治疗反应的预测生物标志物、靶向肿瘤微环境以及探索新型治疗药物和个性化医疗策略。更深入地了解这些机制对于开发更有效的治疗方法和改善晚期HCC患者的预后至关重要。本文讨论了可能用于提高治疗成功率的策略，并总结了关于导致索拉非尼耐药的可能途径的新研究。
