靶向 Aurora A 克服头颈癌的顺铂抗药性

X Li, Z Wang, G G Oakley, L Wang, E A Lanzel, M R Buchakjian, A Peng
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引用次数: 0

摘要

以顺铂为基础的化疗是晚期复发性头颈部鳞状细胞癌(HNSCC)的基础治疗。然而,治疗的有效性往往受到内在和获得性耐药和相关毒性的阻碍,突出了迫切的未满足的临床需求。在这里,我们的化合物筛选确定了极光激酶抑制剂,特别是针对极光A激酶的抑制剂,作为使耐药的HNSCC细胞对顺铂敏感的潜在药物。虽然极光激酶是公认的有丝分裂的调节因子,但它们在顺铂耐药中的确切作用在很大程度上是未知的,因为顺铂主要在进行DNA复制的细胞中产生毒性。我们证实,Aurora A或其激活剂的消耗增强了耐药HNSCC细胞的顺铂反应。综合数据库和局部治疗的HNSCC患者样本的分析显示,极光a过表达/激活与顺铂耐药、肿瘤复发和不良患者生存率之间存在令人信服的关联。在细胞实验和HNSCC同基因小鼠肿瘤模型中,Aurora A的药理抑制作用与顺铂治疗有效协同。在机制上,Aurora A抑制增强了顺铂治疗后的细胞凋亡诱导,特别是在s期细胞中;诱导复制应激;并抑制顺铂诱导的DNA交联修复。综上所述,我们的发现揭示了极光A激酶在有丝分裂调节之外的重要功能。Aurora A的多重作用表明其作为主要抗癌药物靶点的潜力。鉴于正在进行的对许多Aurora抑制剂用于癌症治疗的研究,探索它们在HNSCC中的临床应用,特别是与铂类药物的联合应用,可能会带来重大的希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer.

Cisplatin-based chemotherapy is a cornerstone treatment for advanced recurrent head and neck squamous cell carcinoma (HNSCC). However, the effectiveness of the treatment is often hindered by intrinsic and acquired resistance and associated toxicity, highlighting a pressing unmet clinical need. Here, our compound screening identified Aurora kinase inhibitors, particularly those targeting Aurora A kinase, as potential agents to sensitize resistant HNSCC cells to cisplatin. While Aurora kinases are well-established regulators of mitosis, their precise role in cisplatin resistance is largely unknown, given that cisplatin confers toxicity primarily in cells undergoing DNA replication. We confirmed that depletion of Aurora A or its activators enhanced cisplatin response in resistant HNSCC cells. Analyses of a comprehensive database and locally treated HNSCC patient samples revealed compelling associations between Aurora A overexpression/activation and cisplatin resistance, tumor recurrence, and poor patient survival. Pharmacologic inhibition of Aurora A effectively synergized with cisplatin treatment in cellular assays and a syngeneic mouse tumor model of HNSCC. Mechanistically, Aurora A inhibition enhanced apoptosis induction after cisplatin treatment, particularly in S-phase cells; induced replication stress; and suppressed the repair of cisplatin-induced DNA crosslinking. Taken together, our findings shed light on important functions of Aurora A kinase beyond mitotic regulation. The multifaceted roles of Aurora A suggest its potential as a prime anticancer drug target. Given the ongoing investigations into numerous Aurora inhibitors for cancer therapy, exploring their clinical applications in HNSCC, especially in combination with platinum drugs, may hold significant promise.

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