Kurihara Eisuke, Shien Kazuhiko, Torigoe Hidejiro, Takeda Tatsuaki, Takahashi Yuta, Ogoshi Yusuke, Yoshioka Takahiro, Namba Kei, Sato Hiroki, Suzawa Ken, Yamamoto Hiromasa, Soh Junichi, Okazaki Mikio, Shien Tadahiko, Tomida Shuta, Toyooka Shinichi
Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
Anticancer Res. 2019 Apr;39(4):1767-1775. doi: 10.21873/anticanres.13283.
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.
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.
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.
Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.
90 kDa热休克蛋白（HSP90）是一种在癌细胞中高表达的伴侣蛋白，参与包括表皮生长因子受体（EGFR）在内的多种客户蛋白的折叠或稳定。ganetespib是一种第二代HSP90抑制剂，对多种癌症类型具有强大的抗肿瘤作用。
本研究检测了ganetespib在EGFR突变的非小细胞肺癌（NSCLC）细胞以及实验建立的具有多种耐药机制（包括EGFR T790M突变、原癌基因met扩增和上皮-间质转化）的EGFR酪氨酸激酶抑制剂（TKI）耐药细胞中的抗肿瘤作用。
Ganetespib在低浓度时显示出强大的抗肿瘤作用，在体外可抑制所有检测的EGFR-TKI耐药细胞系中与EGFR相关的下游通路分子，并诱导多聚ADP-核糖聚合酶的裂解。Ganetespib还抑制了携带EGFR T790M的耐药细胞的体内肿瘤生长。
Ganetespib可能是治疗EGFR-TKI耐药NSCLC患者的一种有前景的治疗选择。
