PMID- 22039466
OWN - NLM
STAT- MEDLINE
DCOM- 20120228
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 10
DP  - 2011
TI  - A mechanism for synergy with combined mTOR and PI3 kinase inhibitors.
PG  - e26343
LID - 10.1371/journal.pone.0026343 [doi]
LID - e26343
AB  - Dysregulation of the mammalian target of rapamycin (mTOR) signaling has been 
      found in many human cancers, particularly those with loss of the tumor suppressor 
      PTEN. However, mTORC1 inhibitors such as temsirolimus have only modest activity 
      when used alone and may induce acquired resistance by activating upstream mTORC2 
      and Akt. Other tumors that do not depend upon PI3K/Akt/mTOR signaling for 
      survival are primarily resistant. This study tested the hypothesis that the 
      limited clinical efficacy of temsirolimus is due to a compensatory increase in 
      survival signaling pathways downstream of Akt as well as an incomplete block of 
      4E-BP1-controlled proliferative processes downstream of mTOR. We explored the 
      addition of a PI3K inhibitor to temsirolimus and identified the mechanism of 
      combinatorial synergy. Proliferation assays revealed that BEZ235 (dual PI3K/mTOR 
      inhibitor) or ZSTK474 (pan PI3K inhibitor) combined with temsirolimus 
      synergistically inhibited cell growth compared to cells treated with any of the 
      agents alone. Co-treatment resulted in G0/G1 cell cycle arrest and up-regulation 
      of p27. Cell death occurred through massive autophagy and subsequent apoptosis. 
      While molecular profiling revealed that, in most cases, sensitivity to 
      temsirolimus alone was most marked in cells with high basal phospho-Akt resulting 
      from PTEN inactivation, combining a PI3K inhibitor with temsirolimus prevented 
      compensatory Akt phosphorylation and synergistically enhanced cell death 
      regardless of PTEN status. Another molecular correlate of synergy was the finding 
      that temsirolimus treatment alone blocks downstream S6 kinase signaling, but not 
      4E-BP1. Adding BEZ235 completely abrogated 4E-BP1 phosphorylation. We conclude 
      that the addition of a PI3K inhibitor overcomes cellular resistance to mTORC1 
      inhibitors regardless of PTEN status, and thus substantially expands the 
      molecular phenotype of tumors likely to respond.
FAU - Yang, Shujie
AU  - Yang S
AD  - Department of Obstetrics & Gynecology, The University of Iowa, Iowa City, Iowa, 
      United States of America.
FAU - Xiao, Xue
AU  - Xiao X
FAU - Meng, Xiangbing
AU  - Meng X
FAU - Leslie, Kimberly K
AU  - Leslie KK
LA  - eng
GR  - R01 CA099908/CA/NCI NIH HHS/United States
GR  - R01CA99908/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111019
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 0 (Triazines)
RN  - 0 (ZSTK474)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Blotting, Western
MH  - Cell Cycle
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - PTEN Phosphohydrolase/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Quinolines/*pharmacology
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Triazines/*pharmacology
PMC - PMC3198385
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/11/01 06:00
MHDA- 2012/03/01 06:00
PMCR- 2011/10/19
CRDT- 2011/11/01 06:00
PHST- 2011/06/06 00:00 [received]
PHST- 2011/09/25 00:00 [accepted]
PHST- 2011/11/01 06:00 [entrez]
PHST- 2011/11/01 06:00 [pubmed]
PHST- 2012/03/01 06:00 [medline]
PHST- 2011/10/19 00:00 [pmc-release]
AID - PONE-D-11-10214 [pii]
AID - 10.1371/journal.pone.0026343 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(10):e26343. doi: 10.1371/journal.pone.0026343. Epub 2011 Oct 19.