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

Author

Listed:
  • Lavinia Arseni

    (German Cancer Research Center (DKFZ))

  • Gianluca Sigismondo

    (German Cancer Research Center
    Heidelberg University, Medical Faculty)

  • Haniyeh Yazdanparast

    (German Cancer Research Center (DKFZ))

  • Johanne U. Hermansen

    (Oslo University Hospital
    University of Oslo)

  • 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
    Department of Hematology)

  • Mikhail M. Savitski

    (Proteomics Core Facility
    Genome Biology Unit)

  • Sigrid S. Skånland

    (Oslo University Hospital
    University of Oslo)

  • Jeroen Krijgsveld

    (German Cancer Research Center
    Heidelberg University, Medical Faculty)

  • Peter Lichter

    (German Cancer Research Center (DKFZ))

  • Martina Seiffert

    (German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • Lavinia Arseni & Gianluca Sigismondo & Haniyeh Yazdanparast & Johanne U. Hermansen & Norman Mack & Sibylle Ohl & Verena Kalter & Murat Iskar & Mathias Kalxdorf & Dennis Friedel & Mandy Rettel & Yashna, 2025. "Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56318-7
    DOI: 10.1038/s41467-025-56318-7
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    References listed on IDEAS

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    1. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Jan A. Burger & Dan A. Landau & Amaro Taylor-Weiner & Ivana Bozic & Huidan Zhang & Kristopher Sarosiek & Lili Wang & Chip Stewart & Jean Fan & Julia Hoellenriegel & Mariela Sivina & Adrian M. Dubuc & , 2016. "Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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