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The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

Author

Listed:
  • Wei Zhou

    (Chinese Academy of Sciences
    Chinese Academy of Science)

  • Wenxi Wang

    (Chinese Academy of Sciences
    UCAS)

  • Yuxin Liang

    (Chinese Academy of Science
    University of Chinese Academy of Sciences)

  • Ruibin Jiang

    (Chinese Academy of Sciences)

  • Fensheng Qiu

    (Chinese Academy of Sciences)

  • Xiying Shao

    (Chinese Academy of Sciences)

  • Yang Liu

    (Chinese Academy of Science
    University of Chinese Academy of Sciences)

  • Le Fang

    (Chinese Academy of Sciences
    UCAS)

  • Maowei Ni

    (Chinese Academy of Sciences)

  • Chenhuan Yu

    (Chinese Academy of Sciences)

  • Yue Zhao

    (Chinese Academy of Sciences)

  • Weijia Huang

    (Chinese Academy of Sciences)

  • Jiong Li

    (Virginia Commonwealth University)

  • Michael J. Donovan

    (Chinese Academy of Sciences)

  • Lina Wang

    (Chinese Academy of Science
    University of Chinese Academy of Sciences)

  • Juan Ni

    (Chinese Academy of Sciences)

  • Dachi Wang

    (Chinese Academy of Sciences)

  • Ting Fu

    (Chinese Academy of Sciences)

  • Jianguo Feng

    (Chinese Academy of Sciences)

  • Xiaojia Wang

    (Chinese Academy of Sciences)

  • Weihong Tan

    (Chinese Academy of Sciences
    UCAS)

  • Xiaohong Fang

    (Chinese Academy of Sciences
    Chinese Academy of Science
    UCAS
    University of Chinese Academy of Sciences)

Abstract

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

Suggested Citation

  • Wei Zhou & Wenxi Wang & Yuxin Liang & Ruibin Jiang & Fensheng Qiu & Xiying Shao & Yang Liu & Le Fang & Maowei Ni & Chenhuan Yu & Yue Zhao & Weijia Huang & Jiong Li & Michael J. Donovan & Lina Wang & J, 2023. "The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39854-y
    DOI: 10.1038/s41467-023-39854-y
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    References listed on IDEAS

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    1. Haizhen Wang & Brandon N. Nicolay & Joel M. Chick & Xueliang Gao & Yan Geng & Hong Ren & Hui Gao & Guizhi Yang & Juliet A. Williams & Jan M. Suski & Mark A. Keibler & Ewa Sicinska & Ulrike Gerdemann &, 2017. "The metabolic function of cyclin D3–CDK6 kinase in cancer cell survival," Nature, Nature, vol. 546(7658), pages 426-430, June.
    2. Luigi Formisano & Yao Lu & Alberto Servetto & Ariella B. Hanker & Valerie M. Jansen & Joshua A. Bauer & Dhivya R. Sudhan & Angel L. Guerrero-Zotano & Sarah Croessmann & Yan Guo & Paula Gonzalez Ericss, 2019. "Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Stefan J. Siira & Henrik Spåhr & Anne-Marie J. Shearwood & Benedetta Ruzzenente & Nils-Göran Larsson & Oliver Rackham & Aleksandra Filipovska, 2017. "LRPPRC-mediated folding of the mitochondrial transcriptome," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    4. Shom Goel & Molly J. DeCristo & April C. Watt & Haley BrinJones & Jaclyn Sceneay & Ben B. Li & Naveed Khan & Jessalyn M. Ubellacker & Shaozhen Xie & Otto Metzger-Filho & Jeremy Hoog & Matthew J. Ellis, 2017. "CDK4/6 inhibition triggers anti-tumour immunity," Nature, Nature, vol. 548(7668), pages 471-475, August.
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