阿法替尼
癌症研究
克拉斯
胰腺癌
表皮生长因子受体
医学
辐射敏感性
埃罗替尼
蛋白激酶B
表皮生长因子受体抑制剂
细胞毒性T细胞
细胞周期
内科学
作者
Florence Huguet,Marie Fernet,Nicole Giocanti,Vincent Favaudon,Annette K. Larsen
标识
DOI:10.1007/s11523-015-0403-8
摘要
Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients. Here we investigated the activity of afatinib, a second-generation irreversible pan-EGFR family kinase inhibitor, alone or in combination with ionizing radiation, toward pancreatic cancer cells. The influence of afatinib on cell proliferation, cell cycle distribution, clonogenic survival, nuclear fragmentation, ploidy, and centrosome amplification following irradiation was determined. Expression and phosphorylation of HER receptors, Akt, DNA-PKcs, and ERK1/2 was characterized by Western blot analysis. Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 (KRAS
wt) and Capan-2 (KRAS
mut) cells, both of which express high levels of EGFR, HER2, and HER3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells, prevented the radio-induced phosphorylation of Akt, and induced mitotic catastrophe following irradiation. In comparison, Panc-1 cells (KRAS
mut) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization. These results must be confirmed in vivo. Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR, HER2, and HER3 receptors, but not with KRAS status.
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