AKT - Clinical Relevance

Clinical Relevance

Akt is associated with tumor cell survival, proliferation, and invasiveness. The activation of Akt is also one of the most frequent alterations observed in human cancer and tumor cells. Tumor cells that have constantly active Akt may depend on Akt for survival. Therefore, understanding Akt and its pathways is important for the creation of better therapies to treat cancer and tumor cells. A mosaic activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with the Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other tissues Because of the Akt functions above Akt inhibitors may treat cancers such as neuroblastoma. Some Akt inhibitors have undergone clinical trials. In 2007 VQD-002 had a phase I trial. In 2010 Perifosine has reached phase II.

Miltefosine is approved for leishmaniasis and under investigation for other indications including HIV.

AKT activation is associated with many malignancies, however, a research group from Massachusetts General Hospital and Harvard University unexpectedly observed a converse role for AKT and one of its downstream effector FOXOs in acute myeloid leukemia (AML). They claimed that low levels of AKT activity associated with elevated levels of FOXOs are required to maintain the function and immature state of leukemia-initiating cells (LICs). FOXOs are active, implying reduced Akt activity, in ∼40% of AML patient samples regardless of genetic subtype; and either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth in mouse model.