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|Ref Type||Journal Article|
|Authors||Vivanco I, Chen ZC, Tanos B, Oldrini B, Hsieh WY, Yannuzzi N, Campos C, Mellinghoff IK|
|Title||A kinase-independent function of AKT promotes cancer cell survival.|
|Abstract Text||The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|AKT1||G311D||missense||unknown||AKT1 G311D lies within the protein kinase domain of the Akt1 protein (UniProt.org). The functional effect of G311D is conflicting as it results in decreased kinase activity, demonstrated by impaired phosphorylation of Akt substrates in cell culture in one study (PMID: 25551293), but results in reduced Akt hydroxylation, increased Akt phosphorylation at T308, and increased colony formation in cell culture in another study (PMID: 27563096).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|AKT1 W80A||breast cancer||resistant||MK2206||Preclinical||Actionable||In a preclinical study, breast cancer cells expressing AKT1 W80A were resistant to MK2206 in culture, resulting in repression of induced cell death when compared to wild-type AKT1 (PMID: 25551293).||25551293|