PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition

PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition
Title:
PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition
Other Titles:
Cancer Cell
Keywords:
Publication Date:
21 July 2016
Citation:
Castel, Pau et al. Cancer Cell , Volume 30 , Issue 2 , 229 - 242
Abstract:
PIK3CA, which encodes the p110a subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3Ka inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Ka inhibitors drives resistance to these agents. However, the mechanism underlying this phenotype is not fully understood. Here we show that in cancer cells resistant to PI3Ka inhibition, PDK1 blockade restores sensitivity to these therapies. SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. Targeting either PDK1 or SGK1 prevents mTORC1 activation, restoring the antitumoral effects of PI3Ka inhibition in resistant cells.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work has been supported by NIH grants P30 CA008748, R01CA190642-01A1, the Breast Cancer Research Foundation, the Geoffrey Beene Cancer Research Center, the A*CRC (A*STAR) and the BMSI (A*STAR) Singapore. D.R.A. and R.B. are supported by the Medical Research Council (MC_UU_12016/2). F.J.C. and E.T. are Terri Brodeur Foundation fellows.
Description:
ISSN:
1535-6108
1878-3686
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