Journal Article

DKFZ-2025-00229

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.

Arseni, L. (First author)DKFZ* ; Sigismondo, G. (First author)DKFZ* ; Yazdanparast, H.DKFZ* ; Hermansen, J. U. ; Mack, N.DKFZ* ; Ohl, S.DKFZ* ; Kalter, V.DKFZ* ; Iskar, M.DKFZ* ; Kalxdorf, M. ; Friedel, D.DKFZ* ; Rettel, M. ; Paul, Y.DKFZ* ; Ringshausen, I. ; Eldering, E. ; Dubois, J. ; Kater, A. P. ; Zapatka, M.DKFZ* ; Roessner, P. M.DKFZ* ; Tausch, E. ; Stilgenbauer, S. ; Dietrich, S. ; Savitski, M. M. ; Skånland, S. S. ; Krijgsveld, J.DKFZ* ; Lichter, P.DKFZ* ; Seiffert, M. (Last author)DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: 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.

Keyword(s): Adenine: analogs & derivatives (MeSH) ; Adenine: therapeutic use (MeSH) ; Adenine: pharmacology (MeSH) ; Leukemia, Lymphocytic, Chronic, B-Cell: drug therapy (MeSH) ; Leukemia, Lymphocytic, Chronic, B-Cell: genetics (MeSH) ; Leukemia, Lymphocytic, Chronic, B-Cell: metabolism (MeSH) ; Piperidines: pharmacology (MeSH) ; Piperidines: therapeutic use (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Proteasome Inhibitors: pharmacology (MeSH) ; Proteasome Inhibitors: therapeutic use (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Drug Resistance, Neoplasm: drug effects (MeSH) ; Oligopeptides: pharmacology (MeSH) ; Oligopeptides: therapeutic use (MeSH) ; Mice (MeSH) ; Pyrimidines: pharmacology (MeSH) ; Pyrimidines: therapeutic use (MeSH) ; Pyrazoles: pharmacology (MeSH) ; Pyrazoles: therapeutic use (MeSH) ; Proteomics (MeSH) ; Proteasome Endopeptidase Complex: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Cell Line, Tumor (MeSH) ; ibrutinib ; carfilzomib ; Adenine ; Piperidines ; Proteasome Inhibitors ; Oligopeptides ; Pyrimidines ; Pyrazoles ; Proteasome Endopeptidase Complex

Note: #EA:B060#EA:B230#LA:B060#

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Contributing Institute(s):

1. B060 Molekulare Genetik (B060)
2. B230 Proteomik von Stammzellen und Krebs (B230)
3. KKE Neuropathologie (B300)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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