将抑制 HSF1 作为克服 Hsp90 治疗耐药性的一种机制

Zachary Chastain, Imade Williams, Vrushabh Ulhaskumar, John Wang, Haddie DeHart, Haimanti Ray, Richard L. Carpenter
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引用次数: 0

摘要

Hsp90 抑制剂曾被尝试用作靶向治疗,但效果不佳。尽管进行了大量临床试验,但目前还没有获得美国食品及药物管理局批准的 Hsp90 抑制剂。众所周知,Hsp90 能将 HSF1 封闭在细胞质中,从而抑制 HSF1(一种致癌转录因子)的活性。我们假设,HSF1 在 Hsp90 抑制作用下被激活是之前的 Hsp90 抑制剂失效的一个重要原因。一旦被释放,HSF1 就会进入细胞核,并驱动许多促进肿瘤发生和发展的过程的表达。我们通过评估癌细胞对 Hsp90 抑制与 HSF1 联合抑制的反应验证了这一假设,从而在抑制 Hsp90 的同时消除了 HSF1 的活性。通过计算卵巢癌细胞(OVCAR8)和乳腺癌细胞(BT474)的联合指数,我们观察到了 Hsp90 抑制(17-DMAG)和 HSF1 抑制(KRIBB11)之间的协同作用。在细胞活力测定中观察到的这种协同作用在球形体形成和克隆生长测定中得到了进一步加强,这些抑制剂的联合作用比单独使用其中一种抑制剂的效果更大。这些结果进一步支持了以下假设:Hsp90 抑制剂的药效会因 HSF1 活性的增加而减弱,HSF1 抑制剂与 Hsp90 抑制剂协同作用可提高药效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of HSF1 as a Mechanism for Overcoming Hsp90 Treatment Resistance
Hsp90 inhibitors have been attempted as a targeted therapy with poor results. Despite numerous clinical trials, there are currently no FDA approved Hsp90 inhibitors available. It is known that Hsp90 sequesters HSF1 in the cytoplasm to suppress HSF1 activity, an oncogenic transcription factor. We hypothesize that HSF1 activation in response to Hsp90 inhibition is a significant reason that previous Hsp90 inhibitors have failed. Once released, HSF1 enters the nucleus and drives expression of many processes that promote the initiation and progression of tumors. This hypothesis was tested by evaluating the response of cancer cells to Hsp90 inhibition with or without combined inhibition of HSF1, thereby removing HSF1 activity as a consequence of Hsp90 inhibition. We observed synergy between Hsp90 inhibition (17-DMAG) and HSF1 inhibition (KRIBB11) from calculation of combination index in ovarian cancer cells (OVCAR8) and breast cancer cells (BT474). This synergy observed in cell viability assays were further reinforced in spheroid formation and clonogenic growth assays where the combination of these inhibitors had a greater effect than either treatment alone. These results further support the hypothesis that Hsp90 inhibition efficacy is mitigated by increased HSF1 activity and that HSF1 inhibitors synergize with Hsp90 inhibitors to improve their efficacy.
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