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

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

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 respo...

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Main Authors: 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, Martina Seiffert
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56318-7
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Summary: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.
ISSN:2041-1723

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