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
{"title":"靶向 Aurora A 克服头颈癌的顺铂抗药性","authors":"X Li, Z Wang, G G Oakley, L Wang, E A Lanzel, M R Buchakjian, A Peng","doi":"10.1177/00220345241309624","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345241309624"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting Aurora A to Overcome Cisplatin Resistance in Head and Neck Cancer.\",\"authors\":\"X Li, Z Wang, G G Oakley, L Wang, E A Lanzel, M R Buchakjian, A Peng\",\"doi\":\"10.1177/00220345241309624\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":94075,\"journal\":{\"name\":\"Journal of dental research\",\"volume\":\" \",\"pages\":\"220345241309624\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-02-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of dental research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1177/00220345241309624\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of dental research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/00220345241309624","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信