Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation

Onoda,Naoyoshi; Nakamura,Masanori; Aomatsu,Naoki; Noda,Satoru; Kashiwagi,Shinichiro; Kurata,Kento; Uchino,Shinya; Hirakawa,Kosei

doi:10.3892/mco.2015.496

Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation

Authors:
- Naoyoshi Onoda
- Masanori Nakamura
- Naoki Aomatsu
- Satoru Noda
- Shinichiro Kashiwagi
- Kento Kurata
- Shinya Uchino
- Kosei Hirakawa
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Affiliations: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Osaka 545‑8585, Japan, Noguchi Thyroid Clinic, Beppu, Oita 874-0932, Japan
Published online on: January 23, 2015 https://doi.org/10.3892/mco.2015.496
Pages: 522-526

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Abstract

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, α 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.

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