Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis
Metastatic BRAF<sup>V600E</sup> colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAF<sup>V600E</sup> 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 BRAF<sup>V600E</sup> 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 BRAF<sup>V600E</sup> CRC.
Authors
- Guoliang Xiao (ORCID: https://orcid.org/0000-0001-5047-8705)
- Maohua Huang (ORCID: https://orcid.org/0009-0007-7653-4403)
- Xiaoxu Zhao (ORCID: https://orcid.org/0000-0001-9746-3770)
- Yunlong Pan
- Shenghui Qiu (ORCID: https://orcid.org/0000-0002-4221-0642)
- Zhan Zhao (ORCID: https://orcid.org/0000-0002-0385-5595)
- Yangzhi Hu (ORCID: https://orcid.org/0000-0003-2600-1442)
- Hui Ding
- Yabing Yang
- Shuchen Huangfu (ORCID: https://orcid.org/0000-0001-8934-5547)
- Shijin Liu (ORCID: https://orcid.org/0000-0002-6194-9557)
- Jinghua Pan (ORCID: https://orcid.org/0000-0003-3741-3397)
- Jiashuai He (ORCID: https://orcid.org/0000-0003-0840-9348)
- Zuyang Chen
- Tongzheng Liu
- Zheng‐Xiang Li (ORCID: https://orcid.org/0000-0003-4350-5976)
- Yiran Zhang (ORCID: https://orcid.org/0000-0003-2621-8908)
- Lu Wang (ORCID: https://orcid.org/0000-0002-3134-2519)
- Hanyang Guan
- Xiangwei Zhang (ORCID: https://orcid.org/0000-0002-7780-9911)
- Qing Wu
- Yanping Wu (ORCID: https://orcid.org/0000-0001-8455-3574)
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Jinan University (CN)
- Ministry of Education (TH)
- Foshan Second People's Hospital (CN)
- First Affiliated Hospital of Jinan University (CN)
- Xiangnan University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s41467-025-58992-z
- Citations
- 14
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hunan Province
- Guangzhou Municipal Science and Technology Project