Ogoshi Yusuke, Shien Kazuhiko, Yoshioka Takahiro, Torigoe Hidejiro, Sato Hiroki, Sakaguchi Masakiyo, Tomida Shuta, Namba Kei, Kurihara Eisuke, Takahashi Yuta, Suzawa Ken, Yamamoto Hiromasa, Soh Junichi, Toyooka Shinichi
Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Oncol Lett. 2019 Mar;17(3):2729-2736. doi: 10.3892/ol.2019.9908. Epub 2019 Jan 8.
Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring alterations was determined and , and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on -altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using -altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of -altered NSCLC.
人表皮生长因子受体2（HER2）是受体酪氨酸激酶ErbB家族的成员。大量研究报道了HER2在包括非小细胞肺癌（NSCLC）在内的多种癌症类型中存在扩增和过表达。然而，HER2靶向治疗的益处尚未完全确立。在本研究中，研究了不可逆的泛HER酪氨酸激酶抑制剂（TKI）奈拉替尼对携带改变的NSCLC细胞的抗肿瘤作用。评估了异位过表达野生型或突变型的正常支气管上皮细胞（BEAS-2B）对奈拉替尼的敏感性。此外，测定了奈拉替尼在几种携带改变的NSCLC细胞系中的抗肿瘤活性，并研究了它们的基因改变与对奈拉替尼治疗敏感性之间的关联。通过蛋白质印迹法测定，异位过表达野生型或突变体（A775insYVMA、G776VC、G776LC、P780insGSP、V659E、G660D和S310F）的BEAS-2B细胞表现出HER2的组成型自磷酸化。虽然这些BEAS-2B细胞对奈拉替尼敏感，但它们对第一代表皮生长因子受体-TKI厄洛替尼不敏感。奈拉替尼对携带改变的（H2170、Calu-3和H1781）NSCLC细胞系也具有抗增殖作用。在使用携带改变的肺癌细胞的小鼠异种移植模型中，奈拉替尼也被证明具有强大的肿瘤生长抑制活性。本研究结果强烈表明，奈拉替尼有潜力成为治疗携带改变的NSCLC的一种有前景的治疗选择。
