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KAKEN_24790822seika.pdf
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網羅的遺伝子解析手法を用いたゲフィチニブ耐性化の機序の解明
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モウラテキ イデンシ カイセキ シュホウ オ モチイタ ゲフィチニブ タイセイカ ノ キジョ ノ カイメイ
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Morateki idenshi kaiseki shuho o mochiita gefichinibu taiseika no kijo no kaimei
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Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis
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寺井, 秀樹
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テライ, ヒデキ
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Terai, Hideki
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慶應義塾大学・医学部・助教
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Research team head
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科研費研究者番号 : 50445293
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2014
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科学研究費補助金研究成果報告書
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2013
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EGFR遺伝子変異を有する非小細胞肺癌細胞はEGFR-TKIに対して高度感受性を示すが、長期間の同薬剤への曝露で耐性獲得が生じることが知られている。その機序の約30%程度は依然不明である。我々はEGFR遺伝子変異を有する非小細胞肺癌細胞株(PC9)に対してEGFR-TKIの一種であるゲフィチニブを低濃度から漸増して長期間曝露することで、耐性細胞株を樹立した。次にその耐性細胞株と従来の感受性細胞株より採取したRNAを用いてcDNAマイクロアレイ解析を行った。その結果、肺癌細胞におけるEGFR-TKIへの耐性獲得の新たな機序としてFGF2-FGFR1経路の活性化の関与が示唆された。
Almost all patients with non-small cell lung cancer who harbor an epidermal growth factor receptor (EGFR) mutation initially respond well to EGFR-tyrosine kinase inhibitors (TKIs) eventually experience relapse. In this study, we have established a gefitinib-resistant cell line model by long-term exposure to gefitinib. We used originally gefitinib-sensitive lung cancer cell lines, namely PC9 and HCC827. We found that the expressions of both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells compared to those in PC9 naïve (PC9 na) cells. We found that proliferation of the PC9 GR cells was dependent on FGF2-FGFR1 pathway. Inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored the gefitinib sensitivity in PC9 GR cells. We propose FGF2-FGFR1 activation through autocrine loop is a novel mechanism of acquiring resistance to EGFR-TKIs and that this loop be targeted to overcome acquired resistance to EGFR-TKIs in a subset of NSCLC patients.
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研究種目 : 若手研究(B)
研究期間 : 2012~2013
課題番号 : 24790822
研究分野 : 医歯薬学
科研費の分科・細目 : 内科系臨床医学・呼吸器内科学
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