with olaparib reporting in 2016. Ipatasertib is in phase II trials for breast cancer. Decreased Akt isoforms can cause deleterious effects Akt isoform 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 a mouse model. Hyperactivation of Akt1 can cause deleterious effects Two studies show that Akt1 is involved in Juvenile Granulosa Cell tumors (JGCT). In-frame duplications in the pleckstrin-homology domain (PHD) of the protein were found in more than 60% of JGCTs occurring in girls under 15 years of age. The JGCTs without duplications carried point mutations affecting highly conserved residues. The mutated proteins carrying the duplications displayed a non-wild-type subcellular distribution, with a marked enrichment at the plasma membrane. This led to a striking degree of Akt1 activation demonstrated by a strong phosphorylation level and corroborated by reporter assays. Analysis by RNA-Seq pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to a possible dedifferentiation process and suggested that most of the transcriptomic dysregulations might be mediated by a limited set of transcription factors perturbed by Akt1 activation. These results incriminate somatic mutations of Akt1 as major probably driver events in the pathogenesis of JGCTs. See also Akt/PKB signaling pathway Discovery and development of mTOR inhibitors PI3K/AKT/mTOR pathway Akt inhibitor PTEN References Further reading External links EC 2.7.11 Protein kinases