Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL

Nat Commun. 2025 Jan 26;16(1):1041. doi: 10.1038/s41467-025-56318-7.

Abstract

Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.

MeSH terms

  • Adenine* / analogs & derivatives
  • Adenine* / pharmacology
  • Adenine* / therapeutic use
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell* / metabolism
  • Mice
  • Oligopeptides* / pharmacology
  • Oligopeptides* / therapeutic use
  • Piperidines* / pharmacology
  • Piperidines* / therapeutic use
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors* / pharmacology
  • Proteasome Inhibitors* / therapeutic use
  • Proteomics
  • Pyrazoles* / pharmacology
  • Pyrazoles* / therapeutic use
  • Pyrimidines* / pharmacology
  • Pyrimidines* / therapeutic use

Substances

  • ibrutinib
  • carfilzomib
  • Adenine
  • Piperidines
  • Proteasome Inhibitors
  • Oligopeptides
  • Pyrimidines
  • Pyrazoles
  • Proteasome Endopeptidase Complex