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Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

Author

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  • Yuen Lam Dora Ng

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Evelyn Ramberger

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Max Delbrück Center for Molecular Medicine
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ))

  • Stephan R. Bohl

    (Ulm University Hospital
    Harvard Medical School)

  • Anna Dolnik

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Christian Steinebach

    (University of Bonn)

  • Theresia Conrad

    (Experimentelle Pharmakologie & Onkologie (EPO) Berlin-Buch GmbH)

  • Sina Müller

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Oliver Popp

    (Max Delbrück Center for Molecular Medicine)

  • Miriam Kull

    (Ulm University Hospital)

  • Mohamed Haji

    (Max Delbrück Center for Molecular Medicine)

  • Michael Gütschow

    (University of Bonn)

  • Hartmut Döhner

    (Ulm University Hospital)

  • Wolfgang Walther

    (Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine)

  • Ulrich Keller

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ)
    Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine
    Berlin Institute of Health (BIH))

  • Lars Bullinger

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ)
    Berlin Institute of Health (BIH))

  • Philipp Mertins

    (Max Delbrück Center for Molecular Medicine
    Berlin Institute of Health (BIH))

  • Jan Krönke

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ))

Abstract

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.

Suggested Citation

  • Yuen Lam Dora Ng & Evelyn Ramberger & Stephan R. Bohl & Anna Dolnik & Christian Steinebach & Theresia Conrad & Sina Müller & Oliver Popp & Miriam Kull & Mohamed Haji & Michael Gütschow & Hartmut Döhne, 2022. "Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28515-1
    DOI: 10.1038/s41467-022-28515-1
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