PMID- 18981735
OWN - NLM
STAT- MEDLINE
DCOM- 20090619
LR  - 20211203
IS  - 1555-8576 (Electronic)
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 7
IP  - 12
DP  - 2008 Dec
TI  - Overcoming mTOR inhibition-induced paradoxical activation of survival signaling 
      pathways enhances mTOR inhibitors' anticancer efficacy.
PG  - 1952-8
AB  - The mammalian target of rapamycin (mTOR) has emerged as an important cancer 
      therapeutic target. Several mTOR inhibitors are currently being tested in cancer 
      clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, 
      inhibition of mTOR activates Akt survival signaling, which in turn attenuates 
      mTOR inhibitors' anticancer efficacy. We are interested in developing strategies 
      for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR 
      inhibition also induced activations of the MEK/ERK signaling pathway in some 
      cancer cell lines after a prolonged treatment. The combination of rapamycin with 
      the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of 
      cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' 
      anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF 
      receptor inhibitor erlotinib synergistically inhibited the growth of both human 
      cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence 
      of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E 
      as well, implying that erlotinib can suppress mTOR inhibition-induced feedback 
      activation of several survival signaling pathways including Akt, ERK and eIF4E. 
      Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer 
      therapy by preventing mTOR inhibition-induced feedback activation of several 
      survival mechanisms.
FAU - Wang, Xuerong
AU  - Wang X
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, Georgia 30322, USA.
FAU - Hawk, Natalyn
AU  - Hawk N
FAU - Yue, Ping
AU  - Yue P
FAU - Kauh, John
AU  - Kauh J
FAU - Ramalingam, Suresh S
AU  - Ramalingam SS
FAU - Fu, Haian
AU  - Fu H
FAU - Khuri, Fadlo R
AU  - Khuri FR
FAU - Sun, Shi-Yong
AU  - Sun SY
LA  - eng
GR  - P01 CA116676-01/CA/NCI NIH HHS/United States
GR  - R01 CA118450-04/CA/NCI NIH HHS/United States
GR  - R01 CA118450-01/CA/NCI NIH HHS/United States
GR  - P01 CA116676/CA/NCI NIH HHS/United States
GR  - R01 CA118450/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20081208
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 624KN6GM2T (temsirolimus)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/therapeutic use
MH  - Antineoplastic Agents/metabolism/*therapeutic use
MH  - Carcinoma, Renal Cell/drug therapy
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Enzyme Inhibitors/pharmacology
MH  - Erlotinib Hydrochloride
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Kidney Neoplasms/drug therapy
MH  - Neoplasms/*drug therapy
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Protein Kinases/*metabolism/therapeutic use
MH  - Quinazolines/therapeutic use
MH  - Signal Transduction
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases
PMC - PMC2762753
MID - NIHMS135561
EDAT- 2008/11/05 09:00
MHDA- 2009/06/20 09:00
PMCR- 2009/12/01
CRDT- 2008/11/05 09:00
PHST- 2008/11/05 09:00 [pubmed]
PHST- 2009/06/20 09:00 [medline]
PHST- 2008/11/05 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - 6944 [pii]
AID - 10.4161/cbt.7.12.6944 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2008 Dec;7(12):1952-8. doi: 10.4161/cbt.7.12.6944. Epub 2008 
      Dec 8.