期刊
CANCER CELL
卷 30, 期 2, 页码 229-242出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.06.004
关键词
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资金
- NIH [P30 CA008748, R01CA190642-01A1]
- Breast Cancer Research Foundation
- Geoffrey Beene Cancer Research Center
- A*CRC (A*STAR)
- BMSI (A*STAR) Singapore
- Medical Research Council [MC_UU_12016/2]
- Medical Research Council [MC_UU_12016/2, MC_U127070193] Funding Source: researchfish
- MRC [MC_UU_12016/2, MC_U127070193] Funding Source: UKRI
PIK3CA, which encodes the p110 alpha subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3K alpha 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 PI3K alpha 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 PI3K alpha 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.
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