PMID- 19372546
OWN - NLM
STAT- MEDLINE
DCOM- 20090608
LR  - 20231105
IS  - 1535-7163 (Print)
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 8
IP  - 4
DP  - 2009 Apr
TI  - Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent 
      and does not predict tumor cell response to PI3K/mTOR inhibition.
PG  - 742-53
LID - 10.1158/1535-7163.MCT-08-0668 [doi]
AB  - Mammalian target of rapamycin (mTOR) regulates cellular processes important for 
      progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) 
      inhibitor, has broad antitumor activity in preclinical models and cancer 
      patients. Although most tumor lines are RAD001 sensitive, some are not. Selective 
      mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving 
      insulin receptor substrate 1, which is suggested to potentially attenuate effects 
      on tumor cell proliferation and viability. Rictor may also play a role because 
      rictor kinase complexes (including mTOR/rictor) regulate AKT S473 
      phosphorylation. The role of raptor and rictor in the in vitro response of human 
      cancer cells to RAD001 was investigated. Using a large panel of cell lines 
      representing different tumor histotypes, the basal phosphorylation of AKT S473 
      and some AKT substrates was found to correlate with the antiproliferative 
      response to RAD001. In contrast, increased AKT S473 phosphorylation induced by 
      RAD001 did not correlate. Similar increases in AKT phosphorylation occurred 
      following raptor depletion using siRNA. Strikingly, rictor down-regulation 
      attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further 
      analyses showed no relationship between modulation of AKT phosphorylation on S473 
      and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I 
      phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in 
      phase I trials, concomitant targeting of these kinases inhibited AKT S473 
      phosphorylation, eliciting more profound cellular responses than mTORC1 
      inhibition alone. However, reduced cell viability could not be predicted from 
      biochemical or cellular responses to mTORC1 inhibitors. These data could have 
      implications for the clinical application of phosphatidylinositol 3-kinase/mTOR 
      inhibitors.
FAU - Breuleux, Madlaina
AU  - Breuleux M
AD  - Novartis Pharma AG, Novartis Institutes for Biomedical Research, Oncology, Basel, 
      Switzerland.
FAU - Klopfenstein, Matthieu
AU  - Klopfenstein M
FAU - Stephan, Christine
AU  - Stephan C
FAU - Doughty, Cheryl A
AU  - Doughty CA
FAU - Barys, Louise
AU  - Barys L
FAU - Maira, Saveur-Michel
AU  - Maira SM
FAU - Kwiatkowski, David
AU  - Kwiatkowski D
FAU - Lane, Heidi A
AU  - Lane HA
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Carrier Proteins)
RN  - 0 (Imidazoles)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Quinolines)
RN  - 0 (RICTOR protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Transcription Factors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Carrier Proteins/*pharmacology
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Everolimus
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Immunoblotting
MH  - Immunosuppressive Agents/pharmacology
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes
MH  - Neoplasms/drug therapy/*metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinases/chemistry/genetics/*metabolism
MH  - Proteins
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Quinolines/pharmacology
MH  - RNA, Small Interfering/pharmacology
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*antagonists & inhibitors
MH  - Tumor Cells, Cultured
PMC - PMC3440776
MID - NIHMS404620
EDAT- 2009/04/18 09:00
MHDA- 2009/06/09 09:00
PMCR- 2012/09/13
CRDT- 2009/04/18 09:00
PHST- 2009/04/18 09:00 [entrez]
PHST- 2009/04/18 09:00 [pubmed]
PHST- 2009/06/09 09:00 [medline]
PHST- 2012/09/13 00:00 [pmc-release]
AID - 8/4/742 [pii]
AID - 10.1158/1535-7163.MCT-08-0668 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2009 Apr;8(4):742-53. doi: 10.1158/1535-7163.MCT-08-0668.