The mechanism of kinase independent AKT in promoting cancer development


The AKT signaling is aberrantly activated in many cancers for promoting tumor development and maintenance. Interestingly, In cancer cells with gain-of-function mutations of MET, HER2 or PI3K, ATP-competitive and allosteric AKT inhibitors performed different efficiency. Vivanco et al. revealed the mechanism and emphasized a kinase-independent function of AKT in regulating cancer cell survival. The article was published in Elife.


In this study, researchers tested the effect of allosteric AKT inhibitor MK2206, and the ATP-competitive AKT inhibitors GSK690693 and GDC0068 in the non-small-cell lung carcinoma (NSCLC) cells line EBC1. A greater cell death rate was induced by the allosteric inhibitor MK2206, than the ATP-competitive AKT inhibitors GSK690693 and GDC0068, indicating a kinase-independent function of AKT contributed to cancer cell maintenance. Moreover, the lack of AKT kinase domain promoted the survival of human melanoma cells and AKT1/AKT2 double knockout cells in a growth-factor independent manner. In addition, the catalytically-inactive AKT perform AKT inhibitor resistance in a PH-domain dependent manner. The findings broaden the previous view of AKT in cancer cells, and contribute to the development of new therapeutic strategies for cancer.


Elife. 2014 Dec 31;3. 10.7554/eLife.03751.

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S1078 MK-2206 2HCl MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. MK-2206 2HCl induces autophagy and apoptosis in cancer cells. Phase 2.
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