Chai Ryan C, Vieusseux Jessica L, Lang Benjamin J, Nguyen Chau H, Kouspou Michelle M, Britt Kara L, Price John T
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia.
Bone Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Mol Oncol. 2017 May;11(5):567-583. doi: 10.1002/1878-0261.12054. Epub 2017 Apr 11.
Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The resultant resistant cell lines maintained their respective levels of resistance (7-240×) in the absence of 17-AAG and were also cross-resistant with other benzoquinone ansamycin HSP90 inhibitors. Expression of members of the histone deacetylase family (HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan-HDAC inhibitors (TSA and LBH589) and the class II HDAC-specific inhibitor SNDX275 were found to resensitize resistant cells towards 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross-resistant towards structurally distinct HSP90 inhibitors such as radicicol and the second-generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 inhibitors. In conclusion, we report that prolonged 17-AAG treatment results in acquired resistance of cancer cells towards not just 17-AAG but also to a spectrum of structurally distinct HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.
热休克蛋白90（HSP90）调节对肿瘤生长至关重要的多种信号通路。因此，HSP90抑制剂在临床前研究中已显示出作为有效的抗癌药物的作用，但由于多种原因，迄今为止在临床试验中尚未观察到相同的效果。造成这种情况的一个潜在原因可能是肿瘤内存在新出现的或获得性耐药。为了研究耐药机制，我们通过逐步提高HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的剂量产生了耐药细胞系。所得的耐药细胞系在不存在17-AAG的情况下保持其各自的耐药水平（7-240倍），并且对其他苯醌安莎霉素HSP90抑制剂也具有交叉耐药性。耐药细胞中组蛋白脱乙酰酶家族成员（HDAC 1、5、6）的表达发生了改变。为了确定HDAC活性是否导致耐药，发现泛HDAC抑制剂（TSA和LBH589）以及II类HDAC特异性抑制剂SNDX275可使耐药细胞对17-AAG和17-二甲基氨基乙氨基-17-去甲氧基格尔德霉素重新敏感。最显著的是，耐药细胞也被鉴定为对结构不同的HSP90抑制剂如放线菌酮以及第二代HSP90抑制剂CCT018159、VER50589和AUY922具有交叉耐药性。HDAC抑制也使耐药细胞对这些类别的HSP90抑制剂重新敏感。总之，我们报告长期17-AAG治疗不仅导致癌细胞对17-AAG产生获得性耐药，而且对一系列结构不同的HSP90抑制剂也产生耐药。这种获得性耐药可以使用临床相关的HDAC抑制剂来抑制。这项工作支持了在临床环境中联合使用HSP90和HDAC抑制剂的潜在益处。
