%0 Journal Article
%A Arseni, Lavinia
%A Sigismondo, Gianluca
%A Yazdanparast, Haniyeh
%A Hermansen, Johanne U
%A Mack, Norman
%A Ohl, Sibylle
%A Kalter, Verena
%A Iskar, Murat
%A Kalxdorf, Mathias
%A Friedel, Dennis
%A Rettel, Mandy
%A Paul, Yashna
%A Ringshausen, Ingo
%A Eldering, Eric
%A Dubois, Julie
%A Kater, Arnon P
%A Zapatka, Marc
%A Roessner, Philipp M
%A Tausch, Eugen
%A Stilgenbauer, Stephan
%A Dietrich, Sascha
%A Savitski, Mikhail M
%A Skånland, Sigrid S
%A Krijgsveld, Jeroen
%A Lichter, Peter
%A Seiffert, Martina
%T Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-00229
%P 1041
%D 2025
%Z #EA:B060#EA:B230#LA:B060#
%X 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.
%K Adenine: analogs & derivatives
%K Adenine: therapeutic use
%K Adenine: pharmacology
%K Leukemia, Lymphocytic, Chronic, B-Cell: drug therapy
%K Leukemia, Lymphocytic, Chronic, B-Cell: genetics
%K Leukemia, Lymphocytic, Chronic, B-Cell: metabolism
%K Piperidines: pharmacology
%K Piperidines: therapeutic use
%K Animals
%K Humans
%K Proteasome Inhibitors: pharmacology
%K Proteasome Inhibitors: therapeutic use
%K Drug Resistance, Neoplasm: genetics
%K Drug Resistance, Neoplasm: drug effects
%K Oligopeptides: pharmacology
%K Oligopeptides: therapeutic use
%K Mice
%K Pyrimidines: pharmacology
%K Pyrimidines: therapeutic use
%K Pyrazoles: pharmacology
%K Pyrazoles: therapeutic use
%K Proteomics
%K Proteasome Endopeptidase Complex: metabolism
%K Disease Models, Animal
%K Female
%K Cell Line, Tumor
%K ibrutinib (NLM Chemicals)
%K carfilzomib (NLM Chemicals)
%K Adenine (NLM Chemicals)
%K Piperidines (NLM Chemicals)
%K Proteasome Inhibitors (NLM Chemicals)
%K Oligopeptides (NLM Chemicals)
%K Pyrimidines (NLM Chemicals)
%K Pyrazoles (NLM Chemicals)
%K Proteasome Endopeptidase Complex (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39863584
%2 pmc:PMC11762753
%R 10.1038/s41467-025-56318-7
%U https://inrepo02.dkfz.de/record/298222