PMID- 26137260
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2049-9450 (Print)
IS  - 2049-9469 (Electronic)
IS  - 2049-9450 (Linking)
VI  - 3
IP  - 3
DP  - 2015 May
TI  - Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic 
      thyroid cancer cell line harboring PI3KCA gene mutation.
PG  - 522-526
AB  - We previously demonstrated the efficacy of gefitinib, a tyrosine kinase inhibitor 
      of the epidermal growth factor receptor (EGFR), on an anaplastic thyroid cancer 
      (ATC) cell line. We also observed that gefitinib was not effective in regulating 
      cell growth in a different ATC cell line that exhibited an altered EGFR-initiated 
      signal transduction pathway. In the present study, we attempted to regulate the 
      downstream effector of EGFR-Akt-mammalian target of rapamycin (mTOR) pathway by 
      an mTOR inhibitor, everolimus. A total of 8 ATC cell lines were employed, 7 of 
      which were established in our institute. OCUT-2 was known to carry a mutation in 
      the phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PI3KCA) and to be 
      gefitinib-resistant, whereas ACT-1 exhibited a remarkable growth arrest by 
      gefitinib. All the cell lines were tested for the cytotoxic effect of everolimus. 
      The mechanisms of cellular toxicity were investigated by EGFR stimulation, cell 
      cycle and concurrent exposure to paclitaxel. In OCUT-2, but not in any of the 
      other cell lines, everolimus achieved a significant growth inhibition (inhibition 
      of 30 and 50% was achieved by concentrations of 0.8 and 5 nM, respectively). The 
      growth in OCUT-2 was inhibited by everolimus, even with concordant EGFR 
      stimulation. This effect was demonstrated by a G2M cell cycle arrest. An additive 
      effect of everolimus onto the cytotoxic effect of paclitaxel was demonstrated at 
      a dose of 1-2 nM. A significant growth inhibitory effect of everolimus on the 
      gefitinib-resistant ATC cell line was demonstrated, suggesting a possible 
      correlation between the efficacy of everolimus and PI3KCA gene mutation and the 
      significance of molecular-targeted therapy in the management of ATC.
FAU - Onoda, Naoyoshi
AU  - Onoda N
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Nakamura, Masanori
AU  - Nakamura M
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Aomatsu, Naoki
AU  - Aomatsu N
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Noda, Satoru
AU  - Noda S
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Kashiwagi, Shinichiro
AU  - Kashiwagi S
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Kurata, Kento
AU  - Kurata K
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
FAU - Uchino, Shinya
AU  - Uchino S
AD  - Noguchi Thyroid Clinic, Beppu, Oita 874-0932, Japan.
FAU - Hirakawa, Kosei
AU  - Hirakawa K
AD  - Department of Surgical Oncology, Osaka City University Graduate School of 
      Medicine, Osaka, Osaka 545-8585, Japan.
LA  - eng
PT  - Journal Article
DEP - 20150123
PL  - England
TA  - Mol Clin Oncol
JT  - Molecular and clinical oncology
JID - 101613422
PMC - PMC4471583
OTO - NOTNLM
OT  - anaplastic thyroid cancer
OT  - cell lines
OT  - everolimus
OT  - mammalian target of rapamycin inhibitor
OT  - resistance
EDAT- 2015/07/03 06:00
MHDA- 2015/07/03 06:01
PMCR- 2015/01/23
CRDT- 2015/07/03 06:00
PHST- 2014/10/06 00:00 [received]
PHST- 2015/01/14 00:00 [accepted]
PHST- 2015/07/03 06:00 [entrez]
PHST- 2015/07/03 06:00 [pubmed]
PHST- 2015/07/03 06:01 [medline]
PHST- 2015/01/23 00:00 [pmc-release]
AID - MCO-0-0-496 [pii]
AID - 10.3892/mco.2015.496 [doi]
PST - ppublish
SO  - Mol Clin Oncol. 2015 May;3(3):522-526. doi: 10.3892/mco.2015.496. Epub 2015 Jan 
      23.