PMID- 23155392
OWN - NLM
STAT- MEDLINE
DCOM- 20130509
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 11
DP  - 2012
TI  - RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth.
PG  - e48548
LID - 10.1371/journal.pone.0048548 [doi]
LID - e48548
AB  - The mammalian target of rapamycin (mTOR) is regulated by oncogenic growth factor 
      signals and plays a pivotal role in controlling cellular metabolism, growth and 
      survival. Everolimus (RAD001) is an allosteric mTOR inhibitor that has shown 
      marked efficacy in certain cancers but is unable to completely inhibit mTOR 
      activity. ATP-competitive mTOR inhibitors such as NVP-BEZ235 can block 
      rapamycin-insensitive mTOR readouts and have entered clinical development as 
      anti-cancer agents. Here, we show the degree to which RAD001 and BEZ235 can be 
      synergistically combined to inhibit mTOR pathway activation, cell proliferation 
      and tumor growth, both in vitro and in vivo. RAD001 and BEZ235 synergized in 
      cancer lines representing different lineages and genetic backgrounds. Strong 
      synergy is seen in neuronal, renal, breast, lung, and haematopoietic cancer cells 
      harboring abnormalities in PTEN, VHL, LKB1, Her2, or KRAS. Critically, in the 
      presence of RAD001, the mTOR-4EBP1 pathway and tumorigenesis can be fully 
      inhibited using lower doses of BEZ235. This is relevant since RAD001 is 
      relatively well tolerated in patients while the toxicity profiles of 
      ATP-competitive mTOR inhibitors are currently unknown.
FAU - Nyfeler, Beat
AU  - Nyfeler B
AD  - Developmental and Molecular Pathways, Novartis Institutes for BioMedical 
      Research, Cambridge, Massachusetts, United States of America.
FAU - Chen, Yan
AU  - Chen Y
FAU - Li, Xiaoyan
AU  - Li X
FAU - Pinzon-Ortiz, Maria
AU  - Pinzon-Ortiz M
FAU - Wang, Zuncai
AU  - Wang Z
FAU - Reddy, Anupama
AU  - Reddy A
FAU - Pradhan, Elina
AU  - Pradhan E
FAU - Das, Rita
AU  - Das R
FAU - Lehar, Joseph
AU  - Lehar J
FAU - Schlegel, Robert
AU  - Schlegel R
FAU - Finan, Peter M
AU  - Finan PM
FAU - Cao, Z Alexander
AU  - Cao ZA
FAU - Murphy, Leon O
AU  - Murphy LO
FAU - Huang, Alan
AU  - Huang A
LA  - eng
PT  - Journal Article
DEP - 20121114
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Quinolines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Transformation, Neoplastic/*drug effects
MH  - Drug Synergism
MH  - Everolimus
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Quinolines/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3498278
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts. Beat Nyfeler, Yan Chen, Xiaoyan Li, Maria Pinzon-Ortiz, 
      Anupama Reddy, Joseph Lehar, Robert Schlegel, Peter M. Finan, Z. Alex Cao, Leon 
      O. Murphy and Alan Huang are employees and/or share holders of Novartis Pharma 
      AG. BEZ235 and RAD001 are either development or marketed products of Novartis 
      Pharma AG. This does not alter the authors' adherence to all the PLOS ONE 
      policies on sharing data and materials, as detailed online in the guide for 
      authors.
EDAT- 2012/11/17 06:00
MHDA- 2013/05/10 06:00
PMCR- 2012/11/14
CRDT- 2012/11/17 06:00
PHST- 2012/03/27 00:00 [received]
PHST- 2012/09/26 00:00 [accepted]
PHST- 2012/11/17 06:00 [entrez]
PHST- 2012/11/17 06:00 [pubmed]
PHST- 2013/05/10 06:00 [medline]
PHST- 2012/11/14 00:00 [pmc-release]
AID - PONE-D-12-08817 [pii]
AID - 10.1371/journal.pone.0048548 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(11):e48548. doi: 10.1371/journal.pone.0048548. Epub 2012 Nov 14.