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

doi:10.1038/s41467-024-49673-4

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

Nat Commun. 2024 Jun 29;15(1):5502. doi: 10.1038/s41467-024-49673-4.

Authors

Chunge Zhong^#^{1

2

3

4}, Wen-Jie Jiang^#⁵, Yingjia Yao^{1

2

3}, Zexu Li^{1

2

3}, You Li^{1

2

3}, Shengnan Wang^{1

2

3}, Xiaofeng Wang^{1

2

3}, Wenjuan Zhu^{1

2

3}, Siqi Wu¹, Jing Wang¹, Shuangshuang Fan^{1

2

3}, Shixin Ma^{1

2

3}, Yeshu Liu¹, Han Zhang^{1

2

3}, Wenchang Zhao^{1

2

3}, Lu Zhao^{1

2

3}, Yi Feng^{1

2

3}, Zihan Li^{1

2

3}, Ruifang Guo¹, Li Yu¹, Fengyun Pei⁶, Jun Hu^{7

8

9}, Xingzhi Feng^{8

9}, Zihuan Yang^{8

9}, Zhengjia Yang¹⁰, Xueying Yang¹¹, Yue Hou¹, Danni Zhang¹², Dake Xu¹², Ren Sheng¹, Yihao Li¹³, Lijun Liu¹, Hua-Jun Wu^{14

15

16}, Jun Huang^{17

18

19

20}, Teng Fei^{21

22

23

24}

Affiliations

¹ Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
² National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang, 110819, China.
³ Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang, 110819, China.
⁴ Foshan Graduate School of Innovation, Northeastern University, Foshan, 528311, China.
⁵ Peking University Third Hospital, Beijing, 100191, China.
⁶ Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁷ Clinical Research Center, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁸ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁹ Guangdong Institute of Gastroenterology, Guangzhou, China.
¹⁰ Department of Cardiothoracic Surgery, Jinqiu Hospital of Liaoning Province, Shenyang, China.
¹¹ Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
¹² Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), School of Materials Science and Engineering, Northeastern University, Shenyang, China.
¹³ BeiGene Institute, BeiGene (Shanghai) Research & Development Co., Ltd, 200131, Shanghai, China.
¹⁴ Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China. hjwu@pku.edu.cn.
¹⁵ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. hjwu@pku.edu.cn.
¹⁶ Center for Precision Medicine Multi-Omics Research, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China. hjwu@pku.edu.cn.
¹⁷ Department of Colorectal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. huangj97@mail.sysu.edu.cn.
¹⁸ Clinical Research Center, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. huangj97@mail.sysu.edu.cn.
¹⁹ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. huangj97@mail.sysu.edu.cn.
²⁰ Guangdong Institute of Gastroenterology, Guangzhou, China. huangj97@mail.sysu.edu.cn.
²¹ Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China. feiteng@mail.neu.edu.cn.
²² National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang, 110819, China. feiteng@mail.neu.edu.cn.
²³ Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang, 110819, China. feiteng@mail.neu.edu.cn.
²⁴ Foshan Graduate School of Innovation, Northeastern University, Foshan, 528311, China. feiteng@mail.neu.edu.cn.

^# Contributed equally.

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.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
CRISPR-Cas Systems* / genetics
Cell Line, Tumor
Clustered Regularly Interspaced Short Palindromic Repeats / genetics
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / genetics
Drug Resistance, Neoplasm* / genetics
Gene Expression Regulation, Neoplastic / drug effects
Humans
Irinotecan* / pharmacology
Mice
Neoplasms / drug therapy
Neoplasms / genetics
Oxaliplatin* / pharmacology
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism

Substances

Antineoplastic Agents
Oxaliplatin
Irinotecan
Protein Serine-Threonine Kinases
PLK4 protein, human

Grants and funding

31871344; 32071441/National Natural Science Foundation of China (National Science Foundation of China)