PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.

Journal Article (Journal Article)

Many patients with multiple myeloma (MM) have comorbidities and are treated with PPAR agonists. Immunomodulatory agents (IMiDs) are the cornerstones for MM therapy. Currently, little is known about how co-administration of PPAR agonists impacts lenalidomide treatment in patients with MM. Here, we determined the effects of PPAR agonists on anti-myeloma activities of lenalidomide in vitro and in a myeloma xenograft mouse model. Genetic overexpression and CRISPR/cas9 knockout experiments were performed to determine the role of CRBN in the PPAR-mediated pathway. A retrospective cohort study was performed to determine the correlation of PPAR expression with the outcomes of patients with MM. PPAR agonists down-regulated CRBN expression and reduced the anti-myeloma efficacy of lenalidomide in vitro and in vivo. Co-treatment with PPAR antagonists increased CRBN expression and improved sensitivity to lenalidomide. PPAR expression was higher in bone marrow cells of patients with newly diagnosed MM than in normal control bone marrow samples. High PPAR expression was correlated with poor clinical outcomes. Our study provides the first evidence that PPARs transcriptionally regulate CRBN and that drug-drug interactions between PPAR agonists and IMiDs may impact myeloma treatment outcomes.

Full Text

Duke Authors

Cited Authors

  • Sha, Y; Wu, J; Paul, B; Zhao, Y; Mathews, P; Li, Z; Norris, J; Wang, E; McDonnell, DP; Kang, Y

Published Date

  • October 1, 2022

Published In

Volume / Issue

  • 545 /

Start / End Page

  • 215832 -

PubMed ID

  • 35872263

Electronic International Standard Serial Number (EISSN)

  • 1872-7980

Digital Object Identifier (DOI)

  • 10.1016/j.canlet.2022.215832


  • eng

Conference Location

  • Ireland