title: mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
abstract: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways.
  
  
  CONCLUSIONS
  The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Vanessa S
authors.initials: VS
authors.lastname: Rodrik-Outmezguine
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Nen C
authors.initials: NC
authors.lastname: Pagano
authors.forename: Poulikos I
authors.initials: PI
authors.lastname: Poulikakos
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moskatel
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guichard
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C493245:CRTC2 protein, human; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol