The hVps34‐SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. (1st August 2016)

• Record Type: Journal Article
• Authors: Bago, Ruzica; Sommer, Eeva; Castel, Pau; Crafter, Claire; Bailey, Fiona P; Shpiro, Natalia; Baselga, José; Cross, Darren; Eyers, Patrick A; Alessi, Dario R
• Is Part Of: EMBO journal. Volume 35:Number 17(2016)
• Page Start: 1902
• Page End: 1922
• Publication Date: 2016-08-01
• Subjects: mTORC1 -- mTORC2 -- NanoString -- PI3K and NDRG1 -- protein kinase inhibitors -- SGK3 -- signal transduction inhibitors; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201693929
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Upon prolonged treatment with class I PI3K or Akt inhibitors breast cancer cells attain resistance and proliferate. As a novel evasive mechanism explaining this phenomenon, the hVps34‐SGK3 pathway maintains mTORC1 activity following sustained inhibition of the PI3K/Akt signalling pathway. Continuous exposure of breast cancer cells to class I PI3K/Akt inhibitors increases expression and activation of the SGK3 kinase. SGK3 activation is controlled by the endosomal lipid kinase hVps34 that generates 3‐phosphoinositide [PI(3)P]. SGK3 possesses a PX domain that binds to PI(3)P, promoting phosphorylation and activation of SGK3 by the PDK1 kinase. SGK3 substitutes for Akt by phosphorylating TSC2, thereby stimulating mTORC1 and leading to tumour progression. Combination of Akt and a novel selective SGK3 inhibitor termed 14h induces regression of BT‐474 breast cancer cell‐derived tumours in a nude mouse xenograft model. Abstract : The hVps34‐SGK3 pathway activates mTORC1 following sustained inhibition of the PI3K/Akt signaling in breast cancer cells, explaining cancer resistance to PI3K signaling inhibitors.