PMID- 21876152
OWN - NLM
STAT- MEDLINE
DCOM- 20111109
LR  - 20220118
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 108
IP  - 37
DP  - 2011 Sep 13
TI  - PI3K-targeted therapy can be evaded by gene amplification along the 
      MYC-eukaryotic translation initiation factor 4E (eIF4E) axis.
PG  - E699-708
LID - 10.1073/pnas.1108237108 [doi]
AB  - The PI3K pathway is frequently activated in cancer; therefore, considerable 
      effort is focused on identifying compounds that can inhibit specific pathway 
      components, particularly the hallmark oncogene PIK3CA. Although targeted 
      inhibition of a cancer survival gene holds significant promise, there are 
      concerns that drug resistance may emerge within the cancerous cells, thus 
      limiting clinical efficacy. Using genetically defined human mammary epithelial 
      cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) 
      inhibitor BEZ235, and by genome-wide copy number analyses, we identified MYC and 
      eIF4E amplification within the resistant cells. Importantly, either MYC or 
      eukaryotic translation initiation factor 4E (eIF4E) was required to bypass 
      pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells 
      displayed elevated 5' cap-dependent protein translation. Collectively, these 
      findings suggest that analysis of drivers of protein translation could facilitate 
      the identification of cancer lesions that confer resistance to PI3K 
      pathway-targeted drugs.
FAU - Ilic, Nina
AU  - Ilic N
AD  - Department of Cancer Biology, Dana-Farber Cancer Institute, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Utermark, Tamara
AU  - Utermark T
FAU - Widlund, Hans R
AU  - Widlund HR
FAU - Roberts, Thomas M
AU  - Roberts TM
LA  - eng
SI  - GEO/GSE25173
GR  - CA089393/CA/NCI NIH HHS/United States
GR  - CA89021/CA/NCI NIH HHS/United States
GR  - P30 CA006516/CA/NCI NIH HHS/United States
GR  - CA030002/CA/NCI NIH HHS/United States
GR  - R37 CA030002/CA/NCI NIH HHS/United States
GR  - P50 CA089393/CA/NCI NIH HHS/United States
GR  - R01 CA030002/CA/NCI NIH HHS/United States
GR  - P01 CA089021/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 - 20110829
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 (CRTC1 protein, human)
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Quinolines)
RN  - 0 (RNA Caps)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Breast Neoplasms/pathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Eukaryotic Initiation Factor-4E/*genetics/metabolism
MH  - Female
MH  - *Gene Amplification/drug effects
MH  - Gene Dosage/genetics
MH  - Genome, Human/genetics
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - *Molecular Targeted Therapy
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Point Mutation/genetics
MH  - Protein Biosynthesis/drug effects
MH  - Proto-Oncogene Proteins c-myc/*genetics/metabolism
MH  - Quinolines/pharmacology
MH  - RNA Caps/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Transcription Factors/antagonists & inhibitors/metabolism
MH  - Up-Regulation/drug effects
PMC - PMC3174675
COIS- Conflict of interest statement: In compliance with Harvard Medical School 
      guidelines, we disclose the consulting relationships: Novartis Pharmaceuticals, 
      Inc. (T.M.R.).
EDAT- 2011/08/31 06:00
MHDA- 2011/11/10 06:00
PMCR- 2012/03/13
CRDT- 2011/08/31 06:00
PHST- 2011/08/31 06:00 [entrez]
PHST- 2011/08/31 06:00 [pubmed]
PHST- 2011/11/10 06:00 [medline]
PHST- 2012/03/13 00:00 [pmc-release]
AID - 1108237108 [pii]
AID - 201108237 [pii]
AID - 10.1073/pnas.1108237108 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E699-708. doi: 
      10.1073/pnas.1108237108. Epub 2011 Aug 29.