Home > Publications database > Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL. > print

001     298222
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024 7 _ |a 10.1038/s41467-025-56318-7
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024 7 _ |a pmid:39863584
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024 7 _ |a pmc:PMC11762753
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037 _ _ |a DKFZ-2025-00229
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Arseni, Lavinia
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245 _ _ |a Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
260 _ _ |a [London]
|c 2025
|b Springer Nature
336 7 _ |a article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a ibrutinib
|0 1X70OSD4VX
|2 NLM Chemicals
650 _ 7 |a carfilzomib
|0 72X6E3J5AR
|2 NLM Chemicals
650 _ 7 |a Adenine
|0 JAC85A2161
|2 NLM Chemicals
650 _ 7 |a Piperidines
|2 NLM Chemicals
650 _ 7 |a Proteasome Inhibitors
|2 NLM Chemicals
650 _ 7 |a Oligopeptides
|2 NLM Chemicals
650 _ 7 |a Pyrimidines
|2 NLM Chemicals
650 _ 7 |a Pyrazoles
|2 NLM Chemicals
650 _ 7 |a Proteasome Endopeptidase Complex
|0 EC 3.4.25.1
|2 NLM Chemicals
650 _ 2 |a Adenine: analogs & derivatives
|2 MeSH
650 _ 2 |a Adenine: therapeutic use
|2 MeSH
650 _ 2 |a Adenine: pharmacology
|2 MeSH
650 _ 2 |a Leukemia, Lymphocytic, Chronic, B-Cell: drug therapy
|2 MeSH
650 _ 2 |a Leukemia, Lymphocytic, Chronic, B-Cell: genetics
|2 MeSH
650 _ 2 |a Leukemia, Lymphocytic, Chronic, B-Cell: metabolism
|2 MeSH
650 _ 2 |a Piperidines: pharmacology
|2 MeSH
650 _ 2 |a Piperidines: therapeutic use
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Proteasome Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Proteasome Inhibitors: therapeutic use
|2 MeSH
650 _ 2 |a Drug Resistance, Neoplasm: genetics
|2 MeSH
650 _ 2 |a Drug Resistance, Neoplasm: drug effects
|2 MeSH
650 _ 2 |a Oligopeptides: pharmacology
|2 MeSH
650 _ 2 |a Oligopeptides: therapeutic use
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Pyrimidines: pharmacology
|2 MeSH
650 _ 2 |a Pyrimidines: therapeutic use
|2 MeSH
650 _ 2 |a Pyrazoles: pharmacology
|2 MeSH
650 _ 2 |a Pyrazoles: therapeutic use
|2 MeSH
650 _ 2 |a Proteomics
|2 MeSH
650 _ 2 |a Proteasome Endopeptidase Complex: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
700 1 _ |a Sigismondo, Gianluca
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700 1 _ |a Yazdanparast, Haniyeh
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700 1 _ |a Hermansen, Johanne U
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700 1 _ |a Mack, Norman
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700 1 _ |a Ohl, Sibylle
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700 1 _ |a Kalter, Verena
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700 1 _ |a Kalxdorf, Mathias
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700 1 _ |a Friedel, Dennis
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700 1 _ |a Rettel, Mandy
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700 1 _ |a Paul, Yashna
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700 1 _ |a Ringshausen, Ingo
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700 1 _ |a Eldering, Eric
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700 1 _ |a Dubois, Julie
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700 1 _ |a Kater, Arnon P
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700 1 _ |a Zapatka, Marc
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700 1 _ |a Roessner, Philipp M
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700 1 _ |a Tausch, Eugen
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700 1 _ |a Stilgenbauer, Stephan
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700 1 _ |a Dietrich, Sascha
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700 1 _ |a Savitski, Mikhail M
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700 1 _ |a Skånland, Sigrid S
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700 1 _ |a Krijgsveld, Jeroen
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700 1 _ |a Lichter, Peter
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700 1 _ |a Seiffert, Martina
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773 _ _ |a 10.1038/s41467-025-56318-7
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