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

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 Döhner, Wolfgang Walther, Ulrich Keller, Lars Bullinger, Philipp Mertins () and Jan Krönke ()
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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
Stephan R. Bohl: Ulm University Hospital
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
Lars Bullinger: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Philipp Mertins: Max Delbrück Center for Molecular Medicine
Jan Krönke: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28515-1

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