PMID- 23431193
OWN - NLM
STAT- MEDLINE
DCOM- 20130502
LR  - 20220311
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 10
DP  - 2013 Mar 5
TI  - Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to 
      effectively inhibit NRAS mutant melanoma in vitro and in vivo.
PG  - 4015-20
LID - 10.1073/pnas.1216013110 [doi]
AB  - Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog 
      (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% 
      of cases. NRAS is thought to activate both mitogen activated protein kinase 
      (MAPK) and PI3K signaling in melanoma cells. We studied the influence of 
      different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) 
      and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant 
      melanoma cells. In general, these cells were more sensitive to MEK inhibition 
      compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and 
      PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell 
      lines tested, suggesting that PI3K signaling is more important for cell survival 
      in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 
      in combination with MEK inhibitors is necessary to effectively abolish growth of 
      NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. 
      Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. 
      Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition 
      predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor 
      receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our 
      results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has 
      antitumor activity and might serve as a therapeutic option in the treatment of 
      NRAS mutant melanoma, for which there are currently no effective therapies.
FAU - Posch, Christian
AU  - Posch C
AD  - Department of Dermatology, Mount Zion Cancer Research Center, San Francisco, CA 
      94115, USA. poschc@derm.ucsf.edu
FAU - Moslehi, Homayoun
AU  - Moslehi H
FAU - Feeney, Luzviminda
AU  - Feeney L
FAU - Green, Gary A
AU  - Green GA
FAU - Ebaee, Anoosheh
AU  - Ebaee A
FAU - Feichtenschlager, Valentin
AU  - Feichtenschlager V
FAU - Chong, Kim
AU  - Chong K
FAU - Peng, Lily
AU  - Peng L
FAU - Dimon, Michelle T
AU  - Dimon MT
FAU - Phillips, Thomas
AU  - Phillips T
FAU - Daud, Adil I
AU  - Daud AI
FAU - McCalmont, Timothy H
AU  - McCalmont TH
FAU - LeBoit, Philip E
AU  - LeBoit PE
FAU - Ortiz-Urda, Susana
AU  - Ortiz-Urda S
LA  - eng
GR  - K08 CA155035/CA/NCI NIH HHS/United States
GR  - 1K08CA155035-01A1/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 - 20130219
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Membrane Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (NRAS protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - Female
MH  - GTP Phosphohydrolases/*genetics
MH  - Humans
MH  - MAP Kinase Signaling System/*drug effects
MH  - Melanoma/*drug therapy/genetics/*metabolism/pathology
MH  - Membrane Proteins/*genetics
MH  - Mice
MH  - Mice, Nude
MH  - Mutation
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/administration & dosage/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC3593920
COIS- The authors declare no conflict of interest.
EDAT- 2013/02/23 06:00
MHDA- 2013/05/03 06:00
PMCR- 2013/09/05
CRDT- 2013/02/23 06:00
PHST- 2013/02/23 06:00 [entrez]
PHST- 2013/02/23 06:00 [pubmed]
PHST- 2013/05/03 06:00 [medline]
PHST- 2013/09/05 00:00 [pmc-release]
AID - 1216013110 [pii]
AID - 201216013 [pii]
AID - 10.1073/pnas.1216013110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4015-20. doi: 
      10.1073/pnas.1216013110. Epub 2013 Feb 19.