PMID- 23891627
OWN - NLM
STAT- MEDLINE
DCOM- 20140106
LR  - 20211203
IS  - 1097-6868 (Electronic)
IS  - 0002-9378 (Linking)
VI  - 209
IP  - 5
DP  - 2013 Nov
TI  - Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the 
      sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective 
      inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2).
PG  - 465.e1-9
LID - S0002-9378(13)00752-7 [pii]
LID - 10.1016/j.ajog.2013.07.020 [doi]
AB  - OBJECTIVE: To evaluate PIK3CA mutational status and c-erbB2 gene amplification in 
      a series of primary uterine serous carcinomas (USC) cell lines. To assess the 
      efficacy of GDC-0980, a potent inhibitor of Class I PI3 kinase and mTOR kinase 
      (TORC1/2), against primary USC harboring HER2/neu gene amplification and/or 
      PIK3CA mutations. STUDY DESIGN: Twenty-two primary USC cell lines were evaluated 
      for c-erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) 
      assays and for PIK3CA gene mutations by direct DNA sequencing of exons 9 and 20. 
      In vitro sensitivity to GDC-0980 was evaluated by flow-cytometry-based viability 
      and proliferation assays. Downstream cellular responses to GDC-0980 were assessed 
      by measuring phosphorylation of the 4-EBP1 protein by flow-cytometry. RESULTS: 
      Five of 22 (22.7%) USC cell lines contained oncogenic PIK3CA mutations although 9 
      (40.9%) harbored c-erbB2 gene amplification by FISH. GDC-0980 caused a strong 
      differential growth inhibition in FISH+ USC when compared with FISH- (GDC-0980 
      IC50 mean +/- SEM = 0.29 +/- 0.05 muM in FISH+ vs 1.09 +/- 0.20 muM in FISH- tumors, P = 
      .02). FISH+ USC harboring PIK3CA mutations were significantly more sensitive to 
      GDC-0980 exposure when compared with USC cell lines harboring wild-type PIK3CA (P 
      = .03). GDC-0980 growth-inhibition was associated with a significant and 
      dose-dependent decline in phosphorylated 4-EBP1 levels. CONCLUSION: Oncogenic 
      PIK3CA mutations and c-erbB2 gene amplification may represent biomarkers to 
      identify patients harboring USC who may benefit most from the use of GDC-0980.
CI  - Copyright (c) 2013 Mosby, Inc. All rights reserved.
FAU - English, Diana P
AU  - English DP
AD  - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University 
      School of Medicine, New Haven, CT.
FAU - Bellone, Stefania
AU  - Bellone S
FAU - Cocco, Emiliano
AU  - Cocco E
FAU - Bortolomai, Ileana
AU  - Bortolomai I
FAU - Pecorelli, Sergio
AU  - Pecorelli S
FAU - Lopez, Salvatore
AU  - Lopez S
FAU - Silasi, Dan-Arin
AU  - Silasi DA
FAU - Schwartz, Peter E
AU  - Schwartz PE
FAU - Rutherford, Thomas
AU  - Rutherford T
FAU - Santin, Alessandro D
AU  - Santin AD
LA  - eng
GR  - CA-16359/CA/NCI NIH HHS/United States
GR  - R01 CA122728-01A4/CA/NCI NIH HHS/United States
GR  - R01 CA154460-01A1/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 - 20130724
PL  - United States
TA  - Am J Obstet Gynecol
JT  - American journal of obstetrics and gynecology
JID - 0370476
RN  - 0 
      (1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*therapeutic use
MH  - Bridged Bicyclo Compounds, Heterocyclic/*therapeutic use
MH  - Carcinoma, Papillary/drug therapy/*genetics
MH  - Cell Line, Tumor
MH  - Class I Phosphatidylinositol 3-Kinases/*antagonists & inhibitors
MH  - Drug Resistance, Neoplasm/genetics
MH  - Endometrial Neoplasms/drug therapy/*genetics
MH  - Female
MH  - Gene Amplification/genetics
MH  - Genes, erbB-2/*genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Middle Aged
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Pyrimidines/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
OTO - NOTNLM
OT  - GDC-0980
OT  - HER2/neu
OT  - PIK3CA
OT  - endometrial neoplasms
OT  - mTOR inhibitor
OT  - uterine serous tumors
EDAT- 2013/07/31 06:00
MHDA- 2014/01/07 06:00
CRDT- 2013/07/30 06:00
PHST- 2013/05/08 00:00 [received]
PHST- 2013/07/06 00:00 [revised]
PHST- 2013/07/22 00:00 [accepted]
PHST- 2013/07/30 06:00 [entrez]
PHST- 2013/07/31 06:00 [pubmed]
PHST- 2014/01/07 06:00 [medline]
AID - S0002-9378(13)00752-7 [pii]
AID - 10.1016/j.ajog.2013.07.020 [doi]
PST - ppublish
SO  - Am J Obstet Gynecol. 2013 Nov;209(5):465.e1-9. doi: 10.1016/j.ajog.2013.07.020. 
      Epub 2013 Jul 24.