Background: Multikinase inhibitors (MKIs) have been shown to improve survival in patients with hepatocellular carcinoma (HCC) compared with placebo. Distinct from other MKIs, cabozantinib has inhibitory activity for both AXL and MET. This review considers the literature elucidating the role of AXL and MET in HCC progression, treatment resistance, and immunomodulation. A systematic search of the PubMed database was conducted on November 16, 2020, and identified a total of 174 search results. A further 36 potentially relevant articles were identified based on the authors’ knowledge. After initial screening by title/abstract, 159 underwent full-text screening and we identified 69 original research articles reporting empirical data from in vitro or in vivo models of HCC evaluating the effects of manipulating AXL or MET signaling on tumorigenic behavior. Summary: AXL expression is highly correlated with HCC progression and outcomes and has been reported to be involved in transforming growth factor-β and the regulation of PI3K/AKT, ERK/MAPK, and CCN proteins. MET protein expression is increased in HCC with the highest histological grade and has been reported to be involved in the regulation of PI3K/AKT, PLCγ/DAG/PKC, and MAPK/ERK signaling. Both AXL and MET are key regulators of sorafenib resistance in HCC. In terms of immunomodulation, there are data to indicate that AXL and MET interact with the immune components of the tumor microenvironment and promote tumorigenesis and treatment resistance. In addition, AXL was found to play a potential role in the development of a protumorigenic neutrophil phenotype in HCC. Combined inhibition of MET and programmed cell death protein resulted in additive reduction of HCC cell growth. Key Messages: AXL and MET play key roles in HCC progression, treatment resistance, and immunomodulation. Continued development of drugs that target these receptor tyrosine kinases appears likely to represent a useful strategy to improve outcomes for patients with HCC.
Liver Cancer

中文翻译：

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肝细胞癌中的 AXL 和 MET：系统文献综述

背景：与安慰剂相比，多激酶抑制剂 (MKI) 已被证明可提高肝细胞癌 (HCC) 患者的生存率。与其他 MKI 不同，卡博替尼对 AXL 和 MET 均具有抑制活性。这篇综述考虑了阐明 AXL 和 MET 在 HCC 进展、治疗抵抗和免疫调节中作用的文献。2020 年 11 月 16 日对 PubMed 数据库进行了系统搜索，共确定了 174 个搜索结果。根据作者的知识确定了另外 36 篇可能相关的文章。在按标题/摘要进行初步筛选后，159 篇文章进行了全文筛选，我们确定了 69 篇原创研究文章，这些文章报告了 HCC 体外或体内模型的经验数据，评估了操纵 AXL 或 MET 信号传导对致瘤行为的影响。概括：AXL 表达与 HCC 进展和结果高度相关，据报道与转化生长因子-β 和 PI3K/AKT、ERK/MAPK 和 CCN 蛋白的调节有关。MET 蛋白表达在具有最高组织学分级的 HCC 中增加，据报道其参与调节 PI3K/AKT、PLCγ/DAG/PKC 和 MAPK/ERK 信号传导。AXL 和 MET 都是 HCC 中索拉非尼耐药的关键调节因子。在免疫调节方面，有数据表明 AXL 和 MET 与肿瘤微环境的免疫成分相互作用，促进肿瘤发生和治疗耐药。此外，发现 AXL 在 HCC 中促瘤性中性粒细胞表型的发展中发挥潜在作用。关键信息： AXL 和 MET 在 HCC 进展、治疗抵抗和免疫调节中发挥关键作用。继续开发针对这些受体酪氨酸激酶的药物似乎可能代表了改善 HCC 患者预后的有用策略。
肝癌