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Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis

Author

Listed:
  • Yiwu Yan

    (Cedars-Sinai Medical Center)

  • Bo Zhou

    (Cedars-Sinai Medical Center
    InterVenn Biosciences)

  • Chen Qian

    (Cedars-Sinai Medical Center)

  • Alex Vasquez

    (Cedars-Sinai Medical Center)

  • Mohini Kamra

    (Purdue University)

  • Avradip Chatterjee

    (Cedars-Sinai Medical Center)

  • Yeon-Joo Lee

    (Cedars-Sinai Medical Center)

  • Xiaopu Yuan

    (Cedars-Sinai Medical Center)

  • Leigh Ellis

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Dolores Vizio

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Edwin M. Posadas

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Natasha Kyprianou

    (Department of Urology, Icahn School of Medicine at Mount Sinai, New York)

  • Beatrice S. Knudsen

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    University of Utah)

  • Kavita Shah

    (Purdue University)

  • Ramachandran Murali

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Arkadiusz Gertych

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Sungyong You

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Michael R. Freeman

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    University of California Los Angeles)

  • Wei Yang

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    University of California Los Angeles)

Abstract

Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.

Suggested Citation

  • Yiwu Yan & Bo Zhou & Chen Qian & Alex Vasquez & Mohini Kamra & Avradip Chatterjee & Yeon-Joo Lee & Xiaopu Yuan & Leigh Ellis & Dolores Vizio & Edwin M. Posadas & Natasha Kyprianou & Beatrice S. Knudse, 2022. "Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28340-6
    DOI: 10.1038/s41467-022-28340-6
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    References listed on IDEAS

    as
    1. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
    2. Catherine S. Grasso & Yi-Mi Wu & Dan R. Robinson & Xuhong Cao & Saravana M. Dhanasekaran & Amjad P. Khan & Michael J. Quist & Xiaojun Jing & Robert J. Lonigro & J. Chad Brenner & Irfan A. Asangani & B, 2012. "The mutational landscape of lethal castration-resistant prostate cancer," Nature, Nature, vol. 487(7406), pages 239-243, July.
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