タキガワ ナギオ
  瀧川 奈義夫
   所属   川崎医科大学  医学部 臨床医学 総合内科学4
   職種   教授
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation
掲載誌名 正式名:Cancer Science
略  称:Cancer Sci
ISSNコード:13479032
巻・号・頁 103(10),1795-1802頁
著者・共著者 Harada Daijiro, Takigawa Nagio, Ochi Nobuaki, Ninomiya Takashi, Yasugi Masayuki,
Kubo Toshio, Takeda Hiromasa, Ichihara Eiki, Ohashi Kadoaki, Takata Saburo, Tanimoto Mitsune, Kiura Katsuyuki
発行年月 2012/10
概要 Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.
DOI 10.1111/j.1349-7006.2012.02363.x
文献番号 22712764