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

Lavinia Arseni, Gianluca Sigismondo, Haniyeh Yazdanparast, Johanne U. Hermansen, Norman Mack, Sibylle Ohl, Verena Kalter, Murat Iskar, Mathias Kalxdorf, Dennis Friedel, Mandy Rettel, Yashna Paul, Ingo Ringshausen, Eric Eldering, Julie Dubois, Arnon P. Kater, Marc Zapatka, Philipp M. Roessner, Eugen Tausch, Stephan Stilgenbauer, Sascha Dietrich, Mikhail M. Savitski, Sigrid S. Skånland, Jeroen Krijgsveld, Peter Lichter and Martina Seiffert ()
Additional contact information
Lavinia Arseni: German Cancer Research Center (DKFZ)
Gianluca Sigismondo: German Cancer Research Center
Haniyeh Yazdanparast: German Cancer Research Center (DKFZ)
Johanne U. Hermansen: Oslo University Hospital
Norman Mack: German Cancer Research Center (DKFZ)
Sibylle Ohl: German Cancer Research Center (DKFZ)
Verena Kalter: German Cancer Research Center (DKFZ)
Murat Iskar: German Cancer Research Center (DKFZ)
Mathias Kalxdorf: a GSK Company
Dennis Friedel: German Cancer Research Center (DKFZ)
Mandy Rettel: Proteomics Core Facility
Yashna Paul: German Cancer Research Center (DKFZ)
Ingo Ringshausen: University of Cambridge
Eric Eldering: University of Amsterdam
Julie Dubois: University of Amsterdam
Arnon P. Kater: University of Amsterdam
Marc Zapatka: German Cancer Research Center (DKFZ)
Philipp M. Roessner: German Cancer Research Center (DKFZ)
Eugen Tausch: Ulm University
Stephan Stilgenbauer: Ulm University
Sascha Dietrich: Department of Hematology
Mikhail M. Savitski: Proteomics Core Facility
Sigrid S. Skånland: Oslo University Hospital
Jeroen Krijgsveld: German Cancer Research Center
Peter Lichter: German Cancer Research Center (DKFZ)
Martina Seiffert: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56318-7

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