Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors
The majority of human cancers harbour mutations promoting activation of the Akt
protein kinase and Akt inhibitors are being evaluated in clinical trials. An important
question concerns understanding the innate mechanisms that confer resistance of
tumour cells to Akt inhibitors. The Serum and Glucocorticoid regulated Kinase
(SGK) is closely related to Akt and controlled by identical upstream regulators (PI 3-
kinase, PDK1 and mTORC2). Mutations that trigger activation of Akt would also
stimulate SGK. Moreover, Akt and SGK possess analogous substrate specificities and
are likely to phosphorylate overlapping substrates to promote proliferation. To
investigate whether cancers possessing high SGK activity could possess innate
resistance to Akt specific inhibitors (that do not target SGK), we analysed SGK levels
and sensitivity of a panel of breast cancer cells towards two distinct Akt inhibitors
currently in clinical trials (AZD5363 and MK-2206). This revealed a number of Akt
inhibitor resistant lines displaying markedly elevated SGK1 that also exhibited
significant phosphorylation of the SGK1 substrate N-myc Downstream-Regulated
Gene 1 (NDRG1). In contrast, most Akt inhibitor sensitive cell lines displayed
low/undetectable levels of SGK1. Intriguingly, despite low SGK1, several Akt
inhibitor sensitive cells showed marked NDRG1 phosphorylation that was, unlike in
the resistant cells, suppressed by Akt inhibitors. SGK1 knockdown markedly reduced
proliferation of A...
Source: BJ Signal - Category: Biochemistry Authors: E M Sommer, H Dry, D Cross, S Guichard, B R Davies, D R Alessi Tags: BJ ChemBio Source Type: research