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: Tags: BJ ChemBio Source Type: research