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

• DOI: 10.1038/s41467-022-28515-1
• Publication Date: 2022-02-23T11:03:09Z
• Authors: 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; Jan Krönke
• Keywords: Cyclin-dependent kinase 6; Pomalidomide; Kinome

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 resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic phosphoproteomic analyses RNA sequencing five paired pre-treatment samples from myeloma patients. These reveal CDK6-governed protein signature that includes high-risk factors such as TRIP13 RRM1. Overexpression CDK6 cell lines reduces sensitivity IMiDs while inhibition by palbociclib or degradation proteolysis targeting chimeras (PROTACs) is synergistic vitro vivo. This work identifies upregulation druggable target IMiD-resistant highlights the use studies uncover cancer.