PMID- 24586420
OWN - NLM
STAT- MEDLINE
DCOM- 20150102
LR  - 20220727
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 2
DP  - 2014
TI  - Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1.
PG  - e88865
LID - 10.1371/journal.pone.0088865 [doi]
LID - e88865
AB  - Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for 
      treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor 
      rapamycin are approved for mantle cell lymphoma but have limited efficacy in 
      other blood cancers. ATP-competitive "active-site" mTOR inhibitors produce more 
      complete mTOR inhibition and are more effective than rapamycin in preclinical 
      models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials 
      of active-site mTOR inhibitors, it will be important to identify resistance 
      mechanisms that might limit drug efficacy in certain patients. From a panel of 
      diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is 
      particularly resistant to apoptosis in the presence of active-site mTOR 
      inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic 
      initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of 
      translation controlled by mTOR. Although VAL cells express the related protein 
      4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G 
      from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, 
      or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with 
      active-site mTOR inhibitors. These findings provide a naturally occurring example 
      of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR 
      inhibitors.
FAU - Mallya, Sharmila
AU  - Mallya S
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
FAU - Fitch, Briana A
AU  - Fitch BA
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
FAU - Lee, J Scott
AU  - Lee JS
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
FAU - So, Lomon
AU  - So L
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
FAU - Janes, Matthew R
AU  - Janes MR
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
FAU - Fruman, David A
AU  - Fruman DA
AD  - Department of Molecular Biology & Biochemistry, and Institute for Immunology, 
      University of California Irvine, Irvine, California United States of America.
LA  - eng
GR  - T32 AI060573/AI/NIAID NIH HHS/United States
GR  - T32 CA009054/CA/NCI NIH HHS/United States
GR  - P30 CA062203/CA/NCI NIH HHS/United States
GR  - R01 CA158383/CA/NCI NIH HHS/United States
GR  - R01-CA158383/CA/NCI NIH HHS/United States
GR  - T32-CA009054/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140221
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Benzoxazoles)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pyrimidines)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EUY85H477I (thiazolyl blue)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*deficiency
MH  - Apoptosis/*drug effects
MH  - Benzoxazoles/pharmacology
MH  - Blotting, Western
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Drug Resistance/physiology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Lymphoma/*metabolism
MH  - Phosphoproteins/*deficiency
MH  - Pyrimidines/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Tetrazolium Salts
MH  - Thiazoles
PMC - PMC3931643
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/04 06:00
MHDA- 2015/01/03 06:00
PMCR- 2014/02/21
CRDT- 2014/03/04 06:00
PHST- 2013/06/14 00:00 [received]
PHST- 2014/01/13 00:00 [accepted]
PHST- 2014/03/04 06:00 [entrez]
PHST- 2014/03/04 06:00 [pubmed]
PHST- 2015/01/03 06:00 [medline]
PHST- 2014/02/21 00:00 [pmc-release]
AID - PONE-D-13-24908 [pii]
AID - 10.1371/journal.pone.0088865 [doi]
PST - epublish
SO  - PLoS One. 2014 Feb 21;9(2):e88865. doi: 10.1371/journal.pone.0088865. eCollection 
      2014.