Nature Communications (Jun 2024)
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,
- Teng Fei
Affiliations
- Chunge Zhong
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Wen-Jie Jiang
- Peking University Third Hospital
- Yingjia Yao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Zexu Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- You Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Shengnan Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Xiaofeng Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Wenjuan Zhu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Siqi Wu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Jing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Shuangshuang Fan
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Shixin Ma
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Yeshu Liu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Han Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Wenchang Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Lu Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Yi Feng
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Zihan Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Ruifang Guo
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Li Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Fengyun Pei
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University
- Jun Hu
- Clinical Research Center, the Sixth Affiliated Hospital, Sun Yat-sen University
- Xingzhi Feng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
- Zihuan Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University
- Zhengjia Yang
- Department of Cardiothoracic Surgery, Jinqiu Hospital of Liaoning Province
- Xueying Yang
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University
- Yue Hou
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Danni Zhang
- Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), School of Materials Science and Engineering, Northeastern University
- Dake Xu
- Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), School of Materials Science and Engineering, Northeastern University
- Ren Sheng
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Yihao Li
- BeiGene Institute, BeiGene (Shanghai) Research & Development Co., Ltd
- Lijun Liu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- Hua-Jun Wu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute
- Jun Huang
- Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University
- Teng Fei
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University
- DOI
- https://doi.org/10.1038/s41467-024-49673-4
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
