Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies.

Keywords: EGFR/PI3K/AKT/mTOR signaling; animal models; hepatocellular carcinoma; targeted therapy.

Figure 1

Schematic illustration of EGFR/PI3K/AKT/mTOR signaling pathway. Receptor dimerization induces the phosphorylation of tyrosine residues at the c-terminal cytoplasmic domain of EGFR. PI3K binds to phosphorylated tyrosine residues on EGFR and converts phosphatidylinositol-4,5-disphosphate (PIP2) in the plasma membrane into phosphatidylinositol-3,4,5-trisphosphate (PIP3), leading to the recruitment and subsequent phosphorylation of AKT by PDK1 and mTORC2. Phosphorylated AKT, in turn, leads to the activation of mTORC1 by regulating the activity of RHEB. Active mTOR induces the phosphorylation and activation of S6K1 and 4EBP1.