IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58992-z.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    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)

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.

Suggested Citation

  • 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 Zh, 2025. "Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58992-z
    DOI: 10.1038/s41467-025-58992-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58992-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58992-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Nicholas Yagoda & Moritz von Rechenberg & Elma Zaganjor & Andras J. Bauer & Wan Seok Yang & Daniel J. Fridman & Adam J. Wolpaw & Inese Smukste & John M. Peltier & J. Jay Boniface & Richard Smith & Ste, 2007. "RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels," Nature, Nature, vol. 447(7146), pages 865-869, June.
    2. Anirudh Prahallad & Chong Sun & Sidong Huang & Federica Di Nicolantonio & Ramon Salazar & Davide Zecchin & Roderick L. Beijersbergen & Alberto Bardelli & René Bernards, 2012. "Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR," Nature, Nature, vol. 483(7387), pages 100-103, March.
    3. Wengui Shi & Gengyuan Zhang & Zhijian Ma & Lianshun Li & Miaomiao Liu & Long Qin & Zeyuan Yu & Lei Zhao & Yang Liu & Xue Zhang & Junjie Qin & Huili Ye & Xiangyan Jiang & Huinian Zhou & Hui Sun & Zuoyi, 2021. "Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Vasanthi S. Viswanathan & Matthew J. Ryan & Harshil D. Dhruv & Shubhroz Gill & Ossia M. Eichhoff & Brinton Seashore-Ludlow & Samuel D. Kaffenberger & John K. Eaton & Kenichi Shimada & Andrew J. Aguirr, 2017. "Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway," Nature, Nature, vol. 547(7664), pages 453-457, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Shaoshuai Tang & Yunzhi Wang & Rongkui Luo & Rundong Fang & Yufeng Liu & Hang Xiang & Peng Ran & Yexin Tong & Mingjun Sun & Subei Tan & Wen Huang & Jie Huang & Jiacheng Lv & Ning Xu & Zhenmei Yao & Qi, 2024. "Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    3. Mathurin Dorel & Bertram Klinger & Tommaso Mari & Joern Toedling & Eric Blanc & Clemens Messerschmidt & Michal Nadler-Holly & Matthias Ziehm & Anja Sieber & Falk Hertwig & Dieter Beule & Angelika Egge, 2021. "Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance," PLOS Computational Biology, Public Library of Science, vol. 17(11), pages 1-26, November.
    4. Bin Huang & Hui Wang & Shuo Liu & Meng Hao & Dan Luo & Yi Zhou & Ying Huang & Yong Nian & Lei Zhang & Bo Chu & Chengqian Yin, 2025. "Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Jin Jin & Qianying Liu & Wei Zheng & Zhenming Shun & Tun Tun Lin & Lei Gao & Yingwen Dong, 2020. "A Bayesian Method for the Detection of Proof of Concept in Early Phase Oncology Studies with a Basket Design," Statistics in Biosciences, Springer;International Chinese Statistical Association, vol. 12(2), pages 167-179, July.
    6. repec:plo:pone00:0038033 is not listed on IDEAS
    7. Gholamreza Safaee Ardekani & Seyed Mehdi Jafarnejad & Larry Tan & Ardavan Saeedi & Gang Li, 2012. "The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 7(10), pages 1-10, October.
    8. Francesca Menghi & Edison T. Liu, 2022. "Functional genomics of complex cancer genomes," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    9. Nathan P. Ward & Sang Jun Yoon & Tyce Flynn & Amanda M. Sherwood & Maddison A. Olley & Juliana Madej & Gina M. DeNicola, 2024. "Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Jun-Yan Li & Yin Zhao & Sha Gong & Miao-Miao Wang & Xu Liu & Qing-Mei He & Ying-Qin Li & Sheng-Yan Huang & Han Qiao & Xi-Rong Tan & Ming-Liang Ye & Xun-Hua Zhu & Shi-Wei He & Qian Li & Ye-Lin Liang & , 2023. "TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Jun Jiang & Lili Yang & Qianqian Xie & Xi Liu & Jie Jiang & Jie Zhang & Shuping Zhang & Huizhen Zheng & Wenjie Li & Xiaoming Cai & Sijin Liu & Ruibin Li, 2024. "Synthetic vectors for activating the driving axis of ferroptosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Shamim Naghdi & Piyush Mishra & Soumya Sinha Roy & David Weaver & Ludivine Walter & Erika Davies & Anil Noronha Antony & Xuena Lin & Gisela Moehren & Mark A. Feitelson & Christopher A. Reed & Tullia L, 2025. "VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    14. Jenna E. Leeuwen & Wail Ba-Alawi & Emily Branchard & Jennifer Cruickshank & Wiebke Schormann & Joseph Longo & Jennifer Silvester & Peter L. Gross & David W. Andrews & David W. Cescon & Benjamin Haibe-, 2022. "Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    15. Heike Chauvistré & Batool Shannan & Sheena M. Daignault-Mill & Robert J. Ju & Daniel Picard & Stefanie Egetemaier & Renáta Váraljai & Christine S. Gibhardt & Antonio Sechi & Farnusch Kaschani & Oliver, 2022. "Persister state-directed transitioning and vulnerability in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    17. Pranavi Koppula & Guang Lei & Yilei Zhang & Yuelong Yan & Chao Mao & Lavanya Kondiparthi & Jiejun Shi & Xiaoguang Liu & Amber Horbath & Molina Das & Wei Li & Masha V. Poyurovsky & Kellen Olszewski & B, 2022. "A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Nneka E. Mbah & Amy L. Myers & Peter Sajjakulnukit & Chan Chung & Joyce K. Thompson & Hanna S. Hong & Heather Giza & Derek Dang & Zeribe C. Nwosu & Mengrou Shan & Stefan R. Sweha & Daniella D. Maydan , 2024. "Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    19. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Yuma Saimoto & Daiki Kusakabe & Kazushi Morimoto & Yuta Matsuoka & Eisho Kozakura & Nao Kato & Kayoko Tsunematsu & Tomohiro Umeno & Tamiko Kiyotani & Shota Matsumoto & Mieko Tsuji & Tasuku Hirayama & , 2025. "Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    21. Dimitri Belenki & Paulina Richter-Pechanska & Zhiting Shao & Animesh Bhattacharya & Andrea Lau & José Américo Nabuco Leva Ferreira de Freitas & Gregor Kandler & Timon P. Hick & Xiurong Cai & Eva Schar, 2025. "Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control," Nature Communications, Nature, vol. 16(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58992-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.