The hVPS34-SGK3 pathway counteracts inhibition of the PI3K-Akt to maintain mTORC1 and tumour growth

Ruzica Bago, Eeva-Liisa Eskelinen, Paul Castel , Claire Crafter, Fiona P Bailey, Natalia Shpiro, Jose Baselga, Darren Cross, Patrick Eyers, Dario Alessi (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)
163 Downloads (Pure)

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 PtdnIns(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.
Original languageEnglish
Pages (from-to)1902-1922
Number of pages23
JournalEMBO Journal
Volume35
Issue number17
Early online date1 Aug 2016
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • mTORC1
  • mTORC2
  • NanoString
  • PI3K and NDRG1
  • protein kinase inhibitors
  • SGK3
  • signal transduction inhibitors

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