Abstract
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 the understanding of the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. SGK (serum- and glucocorticoid-regulated kinase) is closely related to Akt and controlled by identical upstream regulators {PI3K (phosphoinositide 3-kinase), PDK1 (phosphoinositide-dependent kinase 1) and mTORC2 [mTOR (mammalian target of rapamycin) complex 2]}. 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 NDRG1 [N-Myc (neuroblastoma-derived Myc) downstream-regulated gene 1]. In contrast, most Akt-inhibitor-sensitive cell lines displayed low/undetectable levels of SGK1. Intriguingly, despite low SGK1 levels, 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 Akt-inhibitor-resistant, but not -sensitive, cells. Furthermore, treatment of Akt-inhibitor-resistant cells with an mTOR inhibitor suppressed proliferation and led to inhibition of SGK1. The results of the present study suggest that monitoring SGK1 levels as well as responses of NDRG1 phosphorylation to Akt inhibitor administration could have a use in predicting the sensitivity of tumours to compounds that target Akt. Our findings highlight the therapeutic potential that SGK inhibitors or dual Akt/SGK inhibitors might have for treatment of cancers displaying elevated SGK activity.
Highlights
Over 70 % of breast cancers possess mutations that trigger activation of the phosphoinositide 3-kinase (PI3K) signalling pathway [1]
To establish whether there was a link between resistance to Akt inhibitors and serum- and glucocorticoid-induced protein kinase 1 (SGK1) expression, we first compared the growth inhibition by 50% (GI50) values mediated by the Akt inhibitor AZD5363 [21] with relative SGK1 mRNA levels in 21 breast cancer cell lines (Figure 1A)
We observe in several breast cancer cells displaying high Akt activity and low SGK1 that N-Myc downstream-regulated gene 1 (NDRG1) is still phosphorylated and that NDRG1 phosphorylation is suppressed by Akt inhibitors
Summary
Over 70 % of breast cancers possess mutations that trigger activation of the PI3K (phosphoinositide 3-kinase) signalling pathway [1]. These include mutations that induce overexpression of receptor tyrosine kinases [e.g. HER-2 (human epidermal growth factor receptor 2)], loss of the tumour suppressor 3-phosphoinositide phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) or constitutively activate PI3K [2]. Given the pivotal role of PI3K signalling in controlling cell growth, survival and proliferation, key components of this pathway, PI3K, mTOR (mammalian target of rapamycin) and Akt, have emerged as promising targets for cancer drug discovery [2,3]. By phosphorylating TSC2 (tuberous sclerosis complex 2) and PRAS40 (proline-rich Akt substrate of 40 kDa), Akt promotes activation of mTORC1 that plays a vital role in orchestrating proliferation responses [8]
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