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The hVps34‐ SGK 3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC 1 and tumour growth
Author(s) -
Bago Ruzica,
Sommer Eeva,
Castel Pau,
Crafter Claire,
Bailey Fiona P,
Shpiro Natalia,
Baselga José,
Cross Darren,
Eyers Patrick A,
Alessi Dario R
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201693929
Subject(s) - library science , pi3k/akt/mtor pathway , protein kinase b , cancer , biology , cancer research , phosphorylation , medicine , signal transduction , genetics , computer science
We explore mechanisms that enable cancer cells to tolerate PI 3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI 3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK 3 that is related to Akt. Under these conditions, SGK 3 is controlled by hV ps34 that generates PtdIns(3)P, which binds to the PX domain of SGK 3 promoting phosphorylation and activation by its upstream PDK 1 activator. Furthermore, under conditions of prolonged PI 3K/Akt pathway inhibition, SGK 3 substitutes for Akt by phosphorylating TSC 2 to activate mTORC 1. We characterise 14h, a compound that inhibits both SGK 3 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 PI 3K/Akt inhibition. Our findings highlight the importance of the hV ps34‐ SGK 3 pathway and suggest it represents a mechanism to counteract inhibition of PI 3K/Akt signalling. The data support the potential of targeting both Akt and SGK as a cancer therapeutic.