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

Nat Commun. 2022 Feb 23;13(1):1009. doi: 10.1038/s41467-022-28515-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Cell Cycle Proteins / metabolism
  • Cyclin-Dependent Kinase 6* / genetics
  • Cyclin-Dependent Kinase 6* / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Immunologic Factors / pharmacology
  • Lenalidomide* / pharmacology
  • Lenalidomide* / therapeutic use
  • Multiple Myeloma* / drug therapy
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / metabolism
  • Neoplasm Recurrence, Local / drug therapy
  • Proteomics
  • Ubiquitin-Protein Ligases / metabolism
  • Up-Regulation

Substances

  • Cell Cycle Proteins
  • Immunologic Factors
  • Ubiquitin-Protein Ligases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • ATPases Associated with Diverse Cellular Activities
  • TRIP13 protein, human
  • Lenalidomide