小柯机器人

近日，美国纪念斯隆凯特琳癌症研究中心Emily H. Cheng团队发现，靶向Aurora B激酶能够预防和克服肺癌对EGFR抑制剂的抗性。相关论文于2021年8月12日在线发表在《癌细胞》杂志上。

研究人员假设，通过联合疗法增强细胞凋亡可以根除癌细胞，从而减少耐药性顽疾的出现。通过对一个由1000个化合物组成的定制库进行高通量筛选，研究人员发现Aurora B激酶抑制剂是奥希替尼诱导细胞凋亡的有效增强剂。从机制上讲，Aurora B抑制剂通过减少Ser87磷酸化稳定BIM，并通过FOXO1/3转激活PUMA。

重要的是，由上皮-间质转化（EMT）引起的奥希替尼耐药性激活了ATR-CHK1-Aurora B信号级联，从而通过激活BIM介导的有丝分裂灾难，这产生了对相应激酶抑制剂的超敏性。对EGFR和Aurora B的联合抑制不仅能有效地消除癌细胞，还能克服EMT以外的抗性。

据悉，EGFR抑制剂在EGFR突变肺癌中的临床成功受到了获得性耐药的限制。

附：英文原文

Title: Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis

Author: Kosuke Tanaka, Helena A. Yu, Shaoyuan Yang, Song Han, S. Duygu Selcuklu, Kwanghee Kim, Shriram Ramani, Yogesh Tengarai Ganesan, Allison Moyer, Sonali Sinha, Yuchen Xie, Kota Ishizawa, Hatice U. Osmanbeyoglu, Yang Lyu, Nitin Roper, Udayan Guha, Charles M. Rudin, Mark G. Kris, James J. Hsieh, Emily H. Cheng

Issue&Volume: 2021-08-12

Abstract: The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance.We hypothesize that enhancing apoptosis through combination therapies can eradicatecancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughputscreening of a custom library of ～1,000 compounds, we discover Aurora B kinase inhibitorsas potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibitionstabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA throughFOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition(EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivityto respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combinedinhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but alsoovercomes resistance beyond EMT.

DOI: 10.1016/j.ccell.2021.07.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00383-4

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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