Hendriks Lizza E L, Dingemans Anne-Marie C
a Department of Pulmonary Diseases, GROW - School for oncology and developmental biology , Maastricht University Medical Center+ , Maastricht , The Netherlands.
Expert Opin Investig Drugs. 2017 May;26(5):541-550. doi: 10.1080/13543784.2017.1302428. Epub 2017 Mar 8.
Cancer cells have a higher need of chaperones than normal cells to prevent the toxic effects of intracellular protein misfolding and aggregation. Heat shock proteins (Hsps) belong to these chaperones; they are classified into families according to molecular size. Hsps are upregulated in many cancers and inhibition can inhibit tumor growth by destabilizing proteins necessary for tumor survival. In non-small cell lung cancer (NSCLC), there are three different Hsp antagonist classes that are in (early) clinical trials: Hsp90, Hsp70 and Hsp27 inhibitors. Areas covered: The rationale to use Hsp inhibitors in NSCLC will be summarized and phase I-III trials will be reviewed. Expert opinion: Several Hsp90 inhibitors have been tested in phase I-III trials, until now none was positive in unselected NSCLC; therefore development of AUY922, ganetespib and retaspimycin was halted. Results seem more promising in molecularly selected patients, especially in ALK-rearranged NSCLC. Hsp27 is overexpressed in squamous NSCLC and is a mechanism of chemotherapy resistance. The Hsp27 inhibitor apatorsen is now tested in squamous NSCLC. No phase II/III data are known for Hsp70 inhibitors. Combination of Hsp inhibitors with heat shock transcription factor 1 inhibitors or focal adhesion kinase inhibitors might be of interest for future trials.
与正常细胞相比，癌细胞对伴侣蛋白有更高的需求，以防止细胞内蛋白质错误折叠和聚集产生的毒性作用。热休克蛋白（Hsps）属于这些伴侣蛋白；它们根据分子大小被分类为不同家族。Hsps在许多癌症中上调，抑制它们可以通过使肿瘤存活所必需的蛋白质不稳定来抑制肿瘤生长。在非小细胞肺癌（NSCLC）中，有三类不同的Hsp拮抗剂正在（早期）临床试验中：Hsp90、Hsp70和Hsp27抑制剂。涵盖领域：将总结在NSCLC中使用Hsp抑制剂的基本原理，并回顾I至III期试验。专家意见：几种Hsp90抑制剂已在I至III期试验中进行了测试，到目前为止，在未选择的NSCLC中没有一种获得阳性结果；因此，AUY922、ganetespib和retaspimycin的研发已停止。在分子选择的患者中，尤其是在ALK重排的NSCLC中，结果似乎更有前景。Hsp27在肺鳞状细胞癌中过表达，是化疗耐药的一种机制。Hsp27抑制剂apatorsen目前正在肺鳞状细胞癌中进行测试。对于Hsp70抑制剂，尚无II/III期数据。Hsp抑制剂与热休克转录因子1抑制剂或粘着斑激酶抑制剂的联合应用可能是未来试验的一个研究方向。
