Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer
Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer
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DOI：
10.21873/anticanres.13283
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发表时间：
2019-04
影响因子：
2
通讯作者：
Eisuke Kurihara;K. Shien;Hidejiro Torigoe;Tatsuaki Takeda;Yuta Takahashi;Y. Ogoshi;T. Yoshioka;K. Namba;Hiroki Sato-;K. Suzawa;H. Yamamoto;J. Soh;M. Okazaki;T. Shien;S. Tomida;S. Toyooka
中科院分区：
文献类型：
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作者：
Eisuke Kurihara;K. Shien;Hidejiro Torigoe;Tatsuaki Takeda;Yuta Takahashi;Y. Ogoshi;T. Yoshioka;K. Namba;Hiroki Sato-;K. Suzawa;H. Yamamoto;J. Soh;M. Okazaki;T. Shien;S. Tomida;S. Toyooka
背景资料：90 kDa热休克蛋白（HSP 90）是一种在癌细胞中高水平表达的伴侣蛋白，参与多种客户蛋白（包括表皮生长因子受体（EGFR））的折叠或稳定。Ganetespib是第二代HSP 90抑制剂，对各种癌症类型具有强效抗肿瘤作用。材料与方法：本研究检查了ganetespib在EGFR突变型非小细胞肺癌（NSCLC）细胞和实验建立的EGFR酪氨酸激酶抑制剂（TKI）耐药细胞中的抗肿瘤作用，这些细胞具有各种耐药机制，包括EGFR T790 M突变、met原癌基因扩增和上皮-间充质转化。结果如下：Ganetespib在低浓度下显示出强效抗肿瘤作用，在体外所有检查的EGFR-TKI耐药细胞系中抑制EGFR相关下游通路分子并诱导聚ADP-核糖聚合酶裂解。Ganetespib还可抑制携带EGFR T790 M的耐药细胞的体内肿瘤生长。结论：Ganetespib可能是治疗EGFR-TKI耐药NSCLC患者的一种有前途的治疗选择。
Background: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. Materials and Methods: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial–mesenchymal transition. Results: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. Conclusion: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.