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; Jinghua Pan

doi:10.1038/s41467-025-58992-z

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

Nat Commun. 2025 Apr 16;16(1):3605. doi: 10.1038/s41467-025-58992-z.

Authors

Zhan Zhao^#¹, Jiashuai He^#¹, Shenghui Qiu^#^{1

2}, Lu Wang^#³, Shuchen Huangfu^#¹, Yangzhi Hu⁴, Qing Wu⁵, Yabing Yang¹, Xiaobo Li⁶, Maohua Huang⁶, Shijin Liu¹, Hanyang Guan¹, Zuyang Chen¹, Xiangwei Zhang¹, Yiran Zhang¹, Hui Ding¹, Xiaoxu Zhao¹, Guandi Xiao⁷, Yunlong Pan¹, Tongzheng Liu⁸, Yanping Wu⁹, Jinghua Pan¹⁰

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, P. R. China.
² State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
³ Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, 510632, P. R. China.
⁴ The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, P.R. China.
⁵ Department of Hepatic-biliary-pancreatic Surgery, The Second People's Hospital of Foshan, Foshan, Guangdong, 528000, P. R. China.
⁶ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China.
⁷ Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, P. R. China.
⁸ State Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China. liutongzheng@jnu.edu.cn.
⁹ Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, P. R. China. wuyanping@jnu.edu.cn.
¹⁰ Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, P. R. China. huajanve@foxmail.com.

^# Contributed equally.

Abstract

Metastatic BRAF^V600E 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^V600E 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^V600E 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^V600E CRC.

MeSH terms

Animals
Cell Cycle Proteins* / antagonists & inhibitors
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Drug Resistance, Neoplasm* / drug effects
Drug Resistance, Neoplasm* / genetics
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Female
Ferroptosis* / drug effects
Ferroptosis* / genetics
Humans
Mice
Mice, Nude
Phospholipid Hydroperoxide Glutathione Peroxidase* / genetics
Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism
Polo-Like Kinase 1
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
Proto-Oncogene Proteins B-raf* / genetics
Proto-Oncogene Proteins B-raf* / metabolism
Proto-Oncogene Proteins* / antagonists & inhibitors
Proto-Oncogene Proteins* / genetics
Proto-Oncogene Proteins* / metabolism
Signal Transduction / drug effects
Xenograft Model Antitumor Assays

Substances

Proto-Oncogene Proteins B-raf
Polo-Like Kinase 1
Proto-Oncogene Proteins
Protein Serine-Threonine Kinases
Cell Cycle Proteins
BRAF protein, human
ErbB Receptors
Phospholipid Hydroperoxide Glutathione Peroxidase
Protein Kinase Inhibitors
EGFR protein, human

Abstract

MeSH terms

Substances

Grants and funding