Abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Sorafenib is the first multi-tyrosine kinase inhibitor approved for HCC and it has represented the standard of care for advanced HCC for almost 10 years, offering a survival benefit when compared to placebo. However, this benefit is limited, showing rare objective responses and a disease control rate approaching 50– 60%, with most patients experiencing disease progression at 6 months. These scant results dictate the urgent need for strategies to overcome both primary and acquired resistance. Herein we report several mechanisms supporting resistance to sorafenib in HCC patients, including activation of oncogenic pathways. Among these, the AKT/mTOR pathway plays a crucial role being at the crossroad of multiple driving events. Autophagy, multidrug-resistant phenotype, hypoxia-related mechanisms and endoplasmic reticulum stress are gaining more and more relevance as crucial events driving the response to anticancer drugs, including sorafenib. Several HCC-specific miRNAs take part to the regulation of these cellular processes. Remarkably, molecularly targeted strategies able to overcome resistance in these settings have also been reported. So far, the vast majority of data has been derived from laboratory studies, which means the need for an extensive validation. Indeed, most of the possible drug associations displaying promising effects in improving sorafenib efficacy herein described derive from preclinical explorations. Notably, data obtained in animal models can be inconsistent with regard to the human disease for efficacy, safety, side effects, best formulation and pharmacokinetics. However, they represent the necessary preliminary step to improve the management of advanced HCC.

Keywords: HCC, sorafenib, microRNA, autophagy


中文翻译：

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阐明 HCC 中索拉非尼耐药的分子基础：当前发现和未来方向

摘要：肝细胞癌 (HCC) 是全球癌症相关死亡的第二大原因。索拉非尼是首个获批用于 HCC 的多酪氨酸激酶抑制剂，近 10 年来一直代表晚期 HCC 的护理标准，与安慰剂相比可提供生存获益。然而，这种益处是有限的，显示出罕见的客观反应和接近 50-60% 的疾病控制率，大多数患者在 6 个月时出现疾病进展。这些微不足道的结果表明迫切需要克服原发性和获得性耐药性的策略。在此，我们报告了支持 HCC 患者对索拉非尼耐药的几种机制，包括致癌途径的激活。其中，AKT/mTOR 通路在多个驾驶事件的十字路口起着至关重要的作用。自噬，多重耐药表型、缺氧相关机制和内质网应激作为推动抗癌药物（包括索拉非尼）反应的关键事件越来越相关。几种 HCC 特异性 miRNA 参与这些细胞过程的调节。值得注意的是，还报道了能够克服这些环境中的耐药性的分子靶向策略。到目前为止，绝大多数数据都来自实验室研究，这意味着需要进行广泛的验证。实际上，本文描述的在提高索拉非尼疗效方面显示出有希望的作用的大多数可能的药物组合都来自临床前探索。值得注意的是，在动物模型中获得的数据可能与人类疾病的疗效、安全性、副作用、最佳配方和药代动力学。然而，它们代表了改善晚期 HCC 管理的必要初步步骤。

关键词： HCC，索拉非尼，microRNA，自噬