AKT as a Therapeutic Target in Cancer

Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and as such, it has been intensively pursued as a therapeutic target. Despite the high frequency of AKT activation in human tumors, the clinical performance of AKT inhibitors remained largely disappointing for many years. However, the recent approval of the AKT inhibitor capivasertib (formerly AZD-5363) for the treatment of breast cancer provides clinical validation of its therapeutic relevance and raises the possibility that AKT inhibitors could still provide clinical benefit either as monotherapy in patients with the rare AKT-E17K mutation or in broader patient populations when combined with other agents. In this chapter, we review the evidence for AKT dependence in human tumors, the importance of genetic and cellular context in AKT dependence, and the challenges of translating AKT inhibition into therapeutic benefit.