Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and its incidence is steadily increasing. The development of HCC is a complex, multi-step process that is accompanied by alterations in multiple signaling cascades. Recent years have seen advancement in understanding molecular signaling pathways that play central roles in hepatocarcinogenesis. Aberrant activation of YAP/TAZ, Hedgehog, or Wnt/β-catenin signaling is frequently found in a subset of HCC patients. Targeting the signaling pathway via small molecule inhibitors could be a promising therapeutic option for the subset of patients. In this review, we will introduce the signaling pathways, discuss their roles in the development of HCC, and propose a therapeutic approach targeting the signaling pathways in the context of HCC. ABSTRACT: Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. To date, receptor tyrosine kinases (RTKs) are the most favored molecular targets for the treatment of HCC, followed by immune checkpoint regulators such as PD-1, PD-L1, and CTLA-4. With less than desirable clinical outcomes from RTK inhibitors as well as immune checkpoint inhibitors (ICI) so far, novel molecular target therapies have been proposed for HCC. In this review, we will introduce diverse molecular signaling pathways that are aberrantly activated in HCC, focusing on YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in HCC.