Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis

Zhan Zhao, Jiashuai He, Shenghui Qiu, Lu Wang, Shuchen Huangfu, Yangzhi Hu, Qing Wu, Yabing Yang, Xiaobo Li, Maohua Huang, Shijin Liu, Hanyang Guan, Zuyang Chen, Xiangwei Zhang, Yiran Zhang, Hui Ding, Xiaoxu Zhao, Guandi Xiao, Yunlong Pan, Tongzheng Liu (), Yanping Wu () and Jinghua Pan ()
Additional contact information
Zhan Zhao: The First Affiliated Hospital of Jinan University
Jiashuai He: The First Affiliated Hospital of Jinan University
Shenghui Qiu: The First Affiliated Hospital of Jinan University
Lu Wang: Jinan University Medical College
Shuchen Huangfu: The First Affiliated Hospital of Jinan University
Yangzhi Hu: The Affiliated Hospital of Xiangnan University
Qing Wu: The Second People’s Hospital of Foshan
Yabing Yang: The First Affiliated Hospital of Jinan University
Xiaobo Li: Jinan University
Maohua Huang: Jinan University
Shijin Liu: The First Affiliated Hospital of Jinan University
Hanyang Guan: The First Affiliated Hospital of Jinan University
Zuyang Chen: The First Affiliated Hospital of Jinan University
Xiangwei Zhang: The First Affiliated Hospital of Jinan University
Yiran Zhang: The First Affiliated Hospital of Jinan University
Hui Ding: The First Affiliated Hospital of Jinan University
Xiaoxu Zhao: The First Affiliated Hospital of Jinan University
Guandi Xiao: Jinan University
Yunlong Pan: The First Affiliated Hospital of Jinan University
Tongzheng Liu: Jinan University
Yanping Wu: Jinan University
Jinghua Pan: The First Affiliated Hospital of Jinan University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1–CBX8–GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.

Date: 2025
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DOI: 10.1038/s41467-025-58992-z

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