Related Experiment Video

Updated: Oct 2, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

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

Yuen Lam Dora Ng1, Evelyn Ramberger1,2,3, Stephan R Bohl4,5

  • 1Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Nature Communications
|February 24, 2022
PubMed

Insights

Immunomodulatory drugs (IMiDs) resistance in multiple myeloma is often non-genetic. Researchers identified CDK6 upregulation as a key driver, suggesting CDK6 inhibition as a potential therapeutic strategy for relapsed patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide are effective multiple myeloma treatments.
  • Most patients eventually develop acquired drug resistance, leading to relapse.
  • Genetic alterations explain only a fraction of IMiD resistance cases.

Purpose of the Study:

  • To investigate non-genetic mechanisms of acquired drug resistance to IMiDs in multiple myeloma.
  • To identify novel therapeutic targets for IMiD-resistant multiple myeloma.

Main Methods:

  • Integrated proteomic, phosphoproteomic (TMT-based), and RNA sequencing analyses.
  • Paired pre-treatment and relapse samples from five multiple myeloma patients.
  • In vitro and in vivo studies using multiple myeloma cell lines and evaluating drug sensitivity.

Main Results:

  • A CDK6-governed protein resistance signature was identified, including high-risk factors TRIP13 and RRM1.
  • CDK6 overexpression reduced sensitivity to IMiDs in multiple myeloma cell lines.
  • CDK6 inhibition (palbociclib) or degradation (PROTACs) showed synergistic effects with IMiDs.

Conclusions:

  • CDK6 upregulation is a druggable target in IMiD-resistant multiple myeloma.
  • Proteomic studies are valuable for uncovering non-genetic cancer drug resistance mechanisms.
  • Targeting CDK6 offers a promising strategy to overcome IMiD resistance in multiple myeloma.

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