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极光激酶A（AURKA）抑制作为一种针对ARID1A突变型结直肠癌的治疗策略显示出前景。

AURKA inhibition shows promise as a therapeutic strategy for ARID1A-mutant colorectal cancer.

作者信息

Qin Rong-Sheng, Li Chun-Tao, Chen Fei, Luo Shu, Wang Chao, Li Jie, Xu Shan, Kang MingWei, Hu Hao-Wen

机构信息

Department of Oncology, Suining First People's Hospital, No. 2, Wentao Road, High-Tech Zone, Suining, 629000, Sichuan, China.

Department of Hepatobiliary and Pancreatic Surgery, The Affilitaed Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.

出版信息

Discov Oncol. 2024 Oct 14;15(1):556. doi: 10.1007/s12672-024-01433-y.

DOI:10.1007/s12672-024-01433-y
PMID:39402330
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11473479/
Abstract

PURPOSE

Mutations in ARID1A frequently occur in colorectal cancer (CRC) cells. However, there are currently no clinical treatment options specifically addressing this aberration. The preliminary in vitro experiments revealed a synthetic lethal interaction between ARID1A and Aurora kinase A (AURKA) in colorectal cancer (CRC) cells.

METHODS

We collected samples from 80 CRC patients and evaluated the efficacy of AURKA inhibitor (AURKAi) using the ATP-tumor chemosensitivity assay (ATP-TCA) on untreated ARID1A-proficient (ARID1A +) and ARID1A-deficient (ARID1A-) CRC patient samples. In addition, we validated this result by a clonogenic assay. Additionally, we examined the effects of AURKA inhibitors on cell cycle progression and apoptosis in ARID1A + and ARID1A- CRC patient samples using flow cytometry.

RESULTS

The results showed that AURKAi selectively inhibited the growth of ARID1A- CRC cells. Furthermore, AURKA inhibitors significantly increased G2/M arrest and induced apoptosis in ARID1A- cells.

CONCLUSION

We believe that AURKAi hold promise as potential therapeutics for ARID1A mutation colorectal cancer patients.

摘要

目的

ARID1A突变在结直肠癌（CRC）细胞中频繁发生。然而，目前尚无专门针对这种异常情况的临床治疗方案。初步的体外实验揭示了结直肠癌（CRC）细胞中ARID1A与极光激酶A（AURKA）之间存在合成致死相互作用。

方法

我们收集了80例CRC患者的样本，并使用ATP肿瘤化学敏感性测定法（ATP-TCA）评估AURKA抑制剂（AURKAi）对未经治疗的ARID1A功能正常（ARID1A +）和ARID1A缺陷（ARID1A-）的CRC患者样本的疗效。此外，我们通过克隆形成试验验证了这一结果。另外，我们使用流式细胞术检查了AURKA抑制剂对ARID1A +和ARID1A- CRC患者样本中细胞周期进程和细胞凋亡的影响。

结果

结果表明，AURKAi选择性抑制ARID1A- CRC细胞的生长。此外，AURKA抑制剂显著增加ARID1A-细胞中的G2/M期阻滞并诱导细胞凋亡。

结论

我们认为，AURKAi有望成为ARID1A突变型结直肠癌患者的潜在治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a38c/11473479/fdc864842984/12672_2024_1433_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a38c/11473479/2690f401f89a/12672_2024_1433_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a38c/11473479/fdc864842984/12672_2024_1433_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a38c/11473479/2690f401f89a/12672_2024_1433_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a38c/11473479/fdc864842984/12672_2024_1433_Fig2_HTML.jpg

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2
Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response.利用合成致死和 DNA 损伤反应治疗 ARID1A 突变型癌症。
J Biomed Sci. 2022 Sep 19;29(1):71. doi: 10.1186/s12929-022-00856-5.
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Roles of ARID1A variations in colorectal cancer: a collaborative review.
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4
Network Meta-analysis of First-Line Systemic Treatment for Patients With Metastatic Colorectal Cancer.网络荟萃分析转移性结直肠癌一线全身治疗患者。
Cancer Control. 2021 Jan-Dec;28:10732748211033497. doi: 10.1177/10732748211033497.
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