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

Cancer Cell. 2016 Aug 8;30(2):229-242. doi: 10.1016/j.ccell.2016.06.004. Epub 2016 Jul 21.

Abstract

PIK3CA, which encodes the p110α subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3Kα 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 PI3Kα 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 PI3Kα 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 PI3Kα inhibition in resistant cells.

MeSH terms

  • Animals
  • Class I Phosphatidylinositol 3-Kinases
  • Humans
  • Immediate-Early Proteins / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Multiprotein Complexes / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Immediate-Early Proteins
  • Multiprotein Complexes
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • serum-glucocorticoid regulated kinase