title: The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth.
abstract: We explore mechanisms that enable cancer cells to tolerate PI3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK3 that is related to Akt. Under these conditions, SGK3 is controlled by hVps34 that generates PtdIns(3)P, which binds to the PX domain of SGK3 promoting phosphorylation and activation by its upstream PDK1 activator. Furthermore, under conditions of prolonged PI3K/Akt pathway inhibition, SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1. We characterise 14h, a compound that inhibits both SGK3 activity and activation in vivo, and show that a combination of Akt and SGK inhibitors induced marked regression of BT-474 breast cancer cell-derived tumours in a xenograft model. Finally, we present the kinome-wide analysis of mRNA expression dynamics induced by PI3K/Akt inhibition. Our findings highlight the importance of the hVps34-SGK3 pathway and suggest it represents a mechanism to counteract inhibition of PI3K/Akt signalling. The data support the potential of targeting both Akt and SGK as a cancer therapeutic.
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK r.bago@dundee.ac.uk d.r.alessi@dundee.ac.uk.
authors.forename: Ruzica
authors.initials: R
authors.lastname: Bago
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Eeva
authors.initials: E
authors.lastname: Sommer
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.affiliation: Oncology iMED, AstraZeneca CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology University of Liverpool, Liverpool, UK.
authors.forename: Fiona P
authors.initials: FP
authors.lastname: Bailey
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shpiro
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Oncology iMED, AstraZeneca CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology University of Liverpool, Liverpool, UK.
authors.forename: Patrick A
authors.identifier: 0000-0002-9220-2966
authors.initials: PA
authors.lastname: Eyers
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK r.bago@dundee.ac.uk d.r.alessi@dundee.ac.uk.
authors.forename: Dario R
authors.identifier: 0000-0002-2140-9185
authors.initials: DR
authors.lastname: Alessi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D058546:Class III Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: NanoString; PI3K and NDRG1; SGK3; mTORC1; mTORC2; protein kinase inhibitors; signal transduction inhibitors