AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review.

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-ß 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.