AKT Isoforms as a Target in Cancer and Immunotherapy

Over the past years, targeted therapies have received tremendous attention in cancer therapy. One of the most frequently targeted pathways is the PI3K/AKT/mTOR signaling pathway that regulates crucial cellular processes including proliferation, survival, and migration. In a wide variety of cancer entities, the PI3K/AKT/mTOR signaling pathway was found to be a critical driver of disease progression, indicating a noteworthy target in cancer therapy. This chapter focuses on targeted therapies against AKT, which is a key enzyme within the PI3K/AKT/mTOR pathway. Although the three different isoforms of AKT, namely AKT1, AKT2, and AKT3, have a high homology, the isoforms exhibit different biological functions. Recently, direct inhibitors against all AKT isoforms as well as selective inhibitors against specific AKT isoforms have been extensively investigated in preclinical work as well as in clinical trials to attenuate proliferation of cancer cells. While no AKT inhibitor has been approved by the FDA for cancer therapy to date, AKT still plays a crucial role in a variety of treatment strategies including immune checkpoint inhibition. In this chapter, we summarize the status of AKT inhibitors either targeting all or specific AKT isoforms. Furthermore, we explain the role of AKT signaling in direct inhibition of tumor cell growth as well as in immune cells and immune checkpoint inhibition.