Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
Curr Opin Oncol. 2014 Mar;26(2):159-64. doi: 10.1097/CCO.0000000000000047.
Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in non-small-cell lung cancer (NSCLC).
Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel.
Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.
热休克蛋白 90（Hsp90）可保护细胞蛋白不被泛素-蛋白酶体系统降解，从而在应激条件下维持其功能。许多癌症中 Hsp90 的表达增加，以确保其恶性表型，包括增殖增加、凋亡减少和转移潜能，这是通过维持表皮生长因子受体（EGFR）、人表皮生长因子受体 2（HER2）、间变性淋巴瘤激酶（ALK）、v-Raf 鼠肉瘤病毒致癌基因同源物 B1（BRAF）、AKT、B 细胞淋巴瘤 2（BCL2）和细胞周期蛋白等蛋白来实现的。本文讨论了 Hsp90 抑制作为非小细胞肺癌（NSCLC）靶向治疗策略的最新进展。
Hsp90 抑制剂在 NSCLC 细胞系和肿瘤异种移植模型中，无论是单独用药还是与其他药物联合用药，均能抑制肿瘤生长并导致肿瘤消退。Hsp90 抑制在 NSCLC 的某些分子亚型中具有特别的疗效，例如 EGFR 突变和 ALK 重排型 NSCLC。IPI-504 和 ganetespib 无论是单独用药还是与多西他赛联合用药，在 NSCLC 中均具有活性。
临床前研究和早期临床试验已经证实了 Hsp90 抑制作为 NSCLC 靶向治疗的疗效。正在进行的试验将进一步确定 Hsp90 抑制剂在 NSCLC 中的应用价值。
