PMID- 23803853
OWN - NLM
STAT- MEDLINE
DCOM- 20130925
LR  - 20220727
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 29
DP  - 2013 Jul 16
TI  - Myc and mTOR converge on a common node in protein synthesis control that confers 
      synthetic lethality in Myc-driven cancers.
PG  - 11988-93
LID - 10.1073/pnas.1310230110 [doi]
AB  - Myc is one of the most commonly deregulated oncogenes in human cancer, yet 
      therapies directly targeting Myc hyperactivation are not presently available in 
      the clinic. The evolutionarily conserved function of Myc in modulating protein 
      synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the 
      protein synthesis capacity of cancer cells directly contributes to their 
      survival, proliferation, and genome instability. Therefore, inhibiting enhanced 
      protein synthesis may represent a highly relevant strategy for the treatment of 
      Myc-dependent human cancers. However, components of the translation machinery 
      that can be exploited as therapeutic targets for Myc-driven cancers remain poorly 
      defined. Here, we uncover a surprising and important functional link between Myc 
      and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic 
      translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of 
      protein synthesis control. Using a pharmacogenetic approach, we find that 
      mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in 
      Myc-dependent tumor initiation and maintenance. We further show that a clinical 
      mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 
      phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological 
      cancers. Additionally, we demonstrate the clinical implications of these results 
      by delineating a significant link between Myc and mTOR-dependent phosphorylation 
      of 4EBP1 and therapeutic response in human lymphomas. Together, these findings 
      reveal that an important mTOR substrate is found hyperactivated downstream of Myc 
      oncogenic activity to promote tumor survival and confers synthetic lethality, 
      thereby revealing a unique therapeutic approach to render Myc druggable in the 
      clinic.
FAU - Pourdehnad, Michael
AU  - Pourdehnad M
AD  - School of Medicine and Department of Urology, Helen Diller Family Comprehensive 
      Cancer Center, University of California, San Francisco, CA 94158, USA.
FAU - Truitt, Morgan L
AU  - Truitt ML
FAU - Siddiqi, Imran N
AU  - Siddiqi IN
FAU - Ducker, Gregory S
AU  - Ducker GS
FAU - Shokat, Kevan M
AU  - Shokat KM
FAU - Ruggero, Davide
AU  - Ruggero D
LA  - eng
GR  - R01 CA140456/CA/NCI NIH HHS/United States
GR  - R01 CA154916/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130626
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 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Benzoxazoles)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Myc protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Pyrimidines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JGH0DF1U03 (sapanisertib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):1760
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - B-Lymphocytes/*physiology
MH  - Benzoxazoles/administration & dosage/*pharmacology
MH  - Blotting, Western
MH  - Carrier Proteins/*metabolism
MH  - Cell Cycle Proteins
MH  - Cell Transformation, Neoplastic/*metabolism
MH  - Eukaryotic Initiation Factors
MH  - Everolimus
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Microarray Analysis
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Biosynthesis/*physiology
MH  - Proto-Oncogene Proteins c-myc/*metabolism
MH  - Pyrimidines/administration & dosage/*pharmacology
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
PMC - PMC3718086
OTO - NOTNLM
OT  - MLN0128
OT  - eIF4E
OT  - eIF4EBP1
OT  - multiple myeloma
COIS- The authors declare no conflict of interest.
EDAT- 2013/06/28 06:00
MHDA- 2013/09/26 06:00
PMCR- 2014/01/16
CRDT- 2013/06/28 06:00
PHST- 2013/06/28 06:00 [entrez]
PHST- 2013/06/28 06:00 [pubmed]
PHST- 2013/09/26 06:00 [medline]
PHST- 2014/01/16 00:00 [pmc-release]
AID - 1310230110 [pii]
AID - 201310230 [pii]
AID - 10.1073/pnas.1310230110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11988-93. doi: 
      10.1073/pnas.1310230110. Epub 2013 Jun 26.