title: PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.
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.
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Ellis
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
authors.forename: Ruzica
authors.initials: R
authors.lastname: Bago
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: Eneda
authors.initials: E
authors.lastname: Toska
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Razavi
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Srinivasaraghavan
authors.initials: S
authors.lastname: Kannan
authors.affiliation: Bioinformatics Institute (A(∗)STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA.
authors.forename: Maura
authors.initials: M
authors.lastname: Dickler
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, Suite M2015, New York, NY 10065, USA. Electronic address: baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: scaltrim@mskcc.org.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D017874:Immediate-Early Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D058570:TOR Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C484760:PIK3CA protein, human