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.