Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

Keywords: AKT; HCC; immune cells; tumor microenvironment.

Figure 1

The possible impact of Akt inhibition on hepatocellular carcinoma and its tumor microenvironment. Akt, expressed as three isoforms, Akt1, Akt2, and Akt3, has been shown to play a role in the progression of cancer by controlling the growth, proliferation, and survival in tumor cells, and by modulating tumor microenvironment (namely CD8+ T cells, regulatory T cells (Tregs), mast cells, neutrophils, and macrophages).