AKT1 and neoplasm: Most, if not all, of these pan-AKT inhibitors, have failed to progress to phase III as monotherapies, highlighting the need for combining AKT inhibitors with other treatments due to the complexity of AKT biology, with tumor cells are possibly adopting alternative signaling circuitries through feedback loops, downstream target alteration, de novo resistance through loss of negative feedback inhibition (discussed previously), and cross-talk between different pathways [301, 329].