PMID- 25124161
OWN - NLM
STAT- MEDLINE
DCOM- 20141222
LR  - 20191210
IS  - 1095-6859 (Electronic)
IS  - 0090-8258 (Linking)
VI  - 135
IP  - 1
DP  - 2014 Oct
TI  - Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous 
      carcinoma in vitro and in vivo.
PG  - 142-8
LID - S0090-8258(14)01259-1 [pii]
LID - 10.1016/j.ygyno.2014.08.006 [doi]
AB  - OBJECTIVES: Uterine serous carcinoma (USC) represents an aggressive variant of 
      endometrial cancer and accounts for a large proportion of deaths annually. 
      HER2/neu amplification is associated with USC in approximately 30-35% of cases. 
      The objective of this study was to determine the sensitivity of a panel of 
      primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 
      and HER2 inhibitor, both in vitro and in vivo. METHODS: HER2/neu amplification 
      was determined by immunohistochemistry (IHC) and fluorescence in situ 
      hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine 
      the effects of neratinib on cell viability, cell cycle distribution and signaling 
      in vitro. Mice harboring HER2/neu amplified xenografts were treated with 
      neratinib to assess the efficacy of the drug in vivo. RESULTS: HER2/neu 
      amplification was noted in 8/24 primary cell lines. Data regarding the efficacy 
      of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified 
      cell lines with similar growth rates. Data revealed that cell lines with HER2/neu 
      amplification were exquisitely more sensitive to neratinib compared to 
      non-amplified cell lines (mean +/- SEM IC50: 0.011muM +/- 0.0008 vs. 0.312muM +/- 0.0456 
      p<0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and 
      resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib 
      treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor 
      growth and improved overall survival compared to vehicle (p=0.0019). CONCLUSIONS: 
      Neratinib may be a potential treatment option for patients harboring HER2/neu 
      amplified USC. Clinical trials for this subset of endometrial cancer patients are 
      warranted.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Schwab, Carlton L
AU  - Schwab CL
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - English, Diana P
AU  - English DP
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Roque, Dana M
AU  - Roque DM
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Bellone, Stefania
AU  - Bellone S
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Lopez, Salvatore
AU  - Lopez S
AD  - Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Alvaro 
      del Portillo, 21-00128 Roma, Rome, Italy.
FAU - Cocco, Emiliano
AU  - Cocco E
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Nicoletti, Roberta
AU  - Nicoletti R
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Rutherford, Thomas J
AU  - Rutherford TJ
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Schwartz, Peter E
AU  - Schwartz PE
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
FAU - Santin, Alessandro D
AU  - Santin AD
AD  - Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of 
      Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address: 
      Alessandro.santin@yale.edu.
LA  - eng
GR  - CA-16359/CA/NCI NIH HHS/United States
GR  - R01 CA154460-01A1/CA/NCI NIH HHS/United States
GR  - U01 CA176067/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140812
PL  - United States
TA  - Gynecol Oncol
JT  - Gynecologic oncology
JID - 0365304
RN  - 0 (Quinolines)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - JJH94R3PWB (neratinib)
SB  - IM
MH  - Animals
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Female
MH  - In Vitro Techniques
MH  - Mice
MH  - Quinolines/pharmacology/*therapeutic use
MH  - Receptor, ErbB-2/*biosynthesis
MH  - Signal Transduction/drug effects
MH  - Uterine Neoplasms/*drug therapy/*metabolism/pathology
OTO - NOTNLM
OT  - ErbB inhibitors
OT  - HER2/neu
OT  - Neratinib
OT  - Small tyrosine kinase inhibitors
OT  - Uterine serous carcinoma
EDAT- 2014/08/16 06:00
MHDA- 2014/12/23 06:00
CRDT- 2014/08/16 06:00
PHST- 2014/05/29 00:00 [received]
PHST- 2014/08/01 00:00 [revised]
PHST- 2014/08/04 00:00 [accepted]
PHST- 2014/08/16 06:00 [entrez]
PHST- 2014/08/16 06:00 [pubmed]
PHST- 2014/12/23 06:00 [medline]
AID - S0090-8258(14)01259-1 [pii]
AID - 10.1016/j.ygyno.2014.08.006 [doi]
PST - ppublish
SO  - Gynecol Oncol. 2014 Oct;135(1):142-8. doi: 10.1016/j.ygyno.2014.08.006. Epub 2014 
      Aug 12.