CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Chunge Zhong, Wen-Jie Jiang, Yingjia Yao, Zexu Li, You Li, Shengnan Wang, Xiaofeng Wang, Wenjuan Zhu, Siqi Wu, Jing Wang, Shuangshuang Fan, Shixin Ma, Yeshu Liu, Han Zhang, Wenchang Zhao, Lu Zhao, Yi Feng, Zihan Li, Ruifang Guo, Li Yu, Fengyun Pei, Jun Hu, Xingzhi Feng, Zihuan Yang, Zhengjia Yang, Xueying Yang, Yue Hou, Danni Zhang, Dake Xu, Ren Sheng, Yihao Li, Lijun Liu, Hua-Jun Wu (), Jun Huang () and Teng Fei ()
Additional contact information
Chunge Zhong: Northeastern University
Wen-Jie Jiang: Peking University Third Hospital
Yingjia Yao: Northeastern University
Zexu Li: Northeastern University
You Li: Northeastern University
Shengnan Wang: Northeastern University
Xiaofeng Wang: Northeastern University
Wenjuan Zhu: Northeastern University
Siqi Wu: Northeastern University
Jing Wang: Northeastern University
Shuangshuang Fan: Northeastern University
Shixin Ma: Northeastern University
Yeshu Liu: Northeastern University
Han Zhang: Northeastern University
Wenchang Zhao: Northeastern University
Lu Zhao: Northeastern University
Yi Feng: Northeastern University
Zihan Li: Northeastern University
Ruifang Guo: Northeastern University
Li Yu: Northeastern University
Fengyun Pei: Sun Yat-sen University
Jun Hu: Sun Yat-sen University
Xingzhi Feng: Sun Yat-sen University
Zihuan Yang: Sun Yat-sen University
Zhengjia Yang: Jinqiu Hospital of Liaoning Province
Xueying Yang: The Fourth Affiliated Hospital of China Medical University
Yue Hou: Northeastern University
Danni Zhang: Northeastern University
Dake Xu: Northeastern University
Ren Sheng: Northeastern University
Yihao Li: BeiGene (Shanghai) Research & Development Co., Ltd
Lijun Liu: Northeastern University
Hua-Jun Wu: Peking University Cancer Hospital & Institute
Jun Huang: Sun Yat-sen University
Teng Fei: Northeastern University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Date: 2024
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DOI: 10.1038/s41467-024-49673-4

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