HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer.
HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer.
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DOI：
10.1002/1878-0261.12883
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发表时间：
2021-04
影响因子：
6.6
通讯作者：
Budillon A
中科院分区：
文献类型：
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作者：
Lombardi R;Sonego M;Pucci B;Addi L;Iannelli F;Capone F;Alfano L;Roca MS;Milone MR;Moccia T;Costa A;Di Gennaro E;Bruzzese F;Baldassarre G;Budillon A
对铂类（Pt）疗法的获得性耐药是上皮性卵巢癌（EOC）患者治疗中未满足的迫切需求。在这里，我们通过无偏蛋白质组学方法表征了获得性 Pt 抗性的三种同基因 EOC 模型（TOV-112D、OVSAHO 和 MDAH-2774）。使用这种方法，我们鉴定了与亲本细胞相比在 Pt 抗性 (Pt-res) 中的几种差异表达蛋白，并且伴侣 HSP90 作为这些蛋白网络的中心枢纽。因此，在所有 Pt-res 细胞中观察到 HSP90 上调，并且热休克蛋白 90 α 亚型敲除使 Pt-res 细胞对顺铂 (CDDP) 治疗重新敏感。此外，在所有测试模型中，使用两种不同抑制剂[17-(烯丙氨基)-17-去甲氧基格尔德霉素 (17AAG) 和 ganetespib] 进行药理学 HSP90 抑制与 CDDP 协同杀死 Pt-res 细胞。从机制上讲，遗传或药理学 HSP90 抑制加上 CDDP 诱导细胞凋亡和增加 DNA 损伤，特别是在 Pt-res 细胞中。重要的是，HSP90 抑制剂 (HSP90i) 的抗肿瘤活性在来自 Pt-res EOC 患者腹水的原代培养物的离体和异种移植模型的体内均得到证实。总的来说，我们的数据表明了一种基于 Pt 化合物加 HSP90i 的创新抗肿瘤策略，以重新挑战 Pt-res EOC 患者，这可能需要进一步的临床评估。通过公正的蛋白质组学，我们确定 HSP90 是铂 (Pt) 耐药性卵巢癌模型的中心枢纽。事实上，遗传和药理学 HSP90 抑制使耐药细胞对 CDDP 治疗敏感，从而增强 DNA 损伤和细胞凋亡。 CDDP 联合抗 HSP90 疗法对 Pt 耐药 (Pt-res) 卵巢癌患者的原代培养物和体内 Pt-res 卵巢癌异种移植小鼠模型的体外原代培养物也有效。
Acquired resistance to platinum (Pt)‐based therapies is an urgent unmet need in the management of epithelial ovarian cancer (EOC) patients. Here, we characterized by an unbiased proteomics method three isogenic EOC models of acquired Pt resistance (TOV‐112D, OVSAHO, and MDAH‐2774). Using this approach, we identified several differentially expressed proteins in Pt‐resistant (Pt‐res) compared to parental cells and the chaperone HSP90 as a central hub of these protein networks. Accordingly, up‐regulation of HSP90 was observed in all Pt‐res cells and heat‐shock protein 90 alpha isoform knockout resensitizes Pt‐res cells to cisplatin (CDDP) treatment. Moreover, pharmacological HSP90 inhibition using two different inhibitors [17‐(allylamino)‐17‐demethoxygeldanamycin (17AAG) and ganetespib] synergizes with CDDP in killing Pt‐res cells in all tested models. Mechanistically, genetic or pharmacological HSP90 inhibition plus CDDP ‐induced apoptosis and increased DNA damage, particularly in Pt‐res cells. Importantly, the antitumor activities of HSP90 inhibitors (HSP90i) were confirmed both ex vivo in primary cultures derived from Pt‐res EOC patients ascites and in vivo in a xenograft model. Collectively, our data suggest an innovative antitumor strategy, based on Pt compounds plus HSP90i, to rechallenge Pt‐res EOC patients that might warrant further clinical evaluation. By unbiased proteomics, we identified HSP90 as a central hub in platinum (Pt)‐resistant ovarian cancer models. Indeed, genetic and pharmacologial HSP90 inhibition sensitized resistant cells to CDDP treatment, potentiating DNA‐damage and apoptosis. Combined CDDP plus anti‐HSP90 therapy is effective also ex vivo on primary cultures from Pt‐resistant (Pt‐res) ovarian cancer patients and in vivo Pt‐res ovarian cancer xenograft mouse model.
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