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

• Published in: Nature communications 2024-06, Vol.15 (1), p.5502-21, Article 5502
• Main Authors: Zhong, Chunge, Jiang, Wen-Jie, Yao, Yingjia, Li, Zexu, Li, You, Wang, Shengnan, Wang, Xiaofeng, Zhu, Wenjuan, Wu, Siqi, Wang, Jing, Fan, Shuangshuang, Ma, Shixin, Liu, Yeshu, Zhang, Han, Zhao, Wenchang, Zhao, Lu, Feng, Yi, Li, Zihan, Guo, Ruifang, Yu, Li, Pei, Fengyun, Hu, Jun, Feng, Xingzhi, Yang, Zihuan, Yang, Zhengjia, Yang, Xueying, Hou, Yue, Zhang, Danni, Xu, Dake, Sheng, Ren, Li, Yihao, Liu, Lijun, Wu, Hua-Jun, Huang, Jun, Fei, Teng
• Format: Article
• Language: English
• Subjects: 13/106; 49/23; 49/47; 49/91; 631/67/68; 631/67/69; 631/92/609; 82/1; 96/109; 96/2; 96/31; 96/34; 96/44; Ablation; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Biomarkers; Cancer; Cell Line, Tumor; Chemoresistance; Chemotherapy; Clustered Regularly Interspaced Short Palindromic Repeats - genetics; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; CRISPR; CRISPR-Cas Systems - genetics; Drug development; Drug resistance; Drug Resistance, Neoplasm - genetics; Evolution; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genomes; Humanities and Social Sciences; Humans; Irinotecan; Irinotecan - pharmacology; Mice; multidisciplinary; Neoplasms - drug therapy; Neoplasms - genetics; Oxaliplatin; Oxaliplatin - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); Target recognition; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49673-4

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. Chemoresistance limits the success of chemotherapy in patients with cancer. Here, the authors perform 30 genome wide CRISPR knockout screens to identify genes associated to resistance against commonly used chemotherapeutics across multiple cancer types, followed by 26 second round CRISPR screens to identify druggable targets of chemoresistance.