TY  - JOUR
AU  - Arseni, Lavinia
AU  - Sigismondo, Gianluca
AU  - Yazdanparast, Haniyeh
AU  - Hermansen, Johanne U
AU  - Mack, Norman
AU  - Ohl, Sibylle
AU  - Kalter, Verena
AU  - Iskar, Murat
AU  - Kalxdorf, Mathias
AU  - Friedel, Dennis
AU  - Rettel, Mandy
AU  - Paul, Yashna
AU  - Ringshausen, Ingo
AU  - Eldering, Eric
AU  - Dubois, Julie
AU  - Kater, Arnon P
AU  - Zapatka, Marc
AU  - Roessner, Philipp M
AU  - Tausch, Eugen
AU  - Stilgenbauer, Stephan
AU  - Dietrich, Sascha
AU  - Savitski, Mikhail M
AU  - Skånland, Sigrid S
AU  - Krijgsveld, Jeroen
AU  - Lichter, Peter
AU  - Seiffert, Martina
TI  - Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00229
SP  - 1041
PY  - 2025
N1  - #EA:B060#EA:B230#LA:B060#
AB  - 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.
KW  - Adenine: analogs & derivatives
KW  - Adenine: therapeutic use
KW  - Adenine: pharmacology
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: drug therapy
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: genetics
KW  - Leukemia, Lymphocytic, Chronic, B-Cell: metabolism
KW  - Piperidines: pharmacology
KW  - Piperidines: therapeutic use
KW  - Animals
KW  - Humans
KW  - Proteasome Inhibitors: pharmacology
KW  - Proteasome Inhibitors: therapeutic use
KW  - Drug Resistance, Neoplasm: genetics
KW  - Drug Resistance, Neoplasm: drug effects
KW  - Oligopeptides: pharmacology
KW  - Oligopeptides: therapeutic use
KW  - Mice
KW  - Pyrimidines: pharmacology
KW  - Pyrimidines: therapeutic use
KW  - Pyrazoles: pharmacology
KW  - Pyrazoles: therapeutic use
KW  - Proteomics
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - Disease Models, Animal
KW  - Female
KW  - Cell Line, Tumor
KW  - ibrutinib (NLM Chemicals)
KW  - carfilzomib (NLM Chemicals)
KW  - Adenine (NLM Chemicals)
KW  - Piperidines (NLM Chemicals)
KW  - Proteasome Inhibitors (NLM Chemicals)
KW  - Oligopeptides (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - Pyrazoles (NLM Chemicals)
KW  - Proteasome Endopeptidase Complex (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39863584
C2  - pmc:PMC11762753
DO  - DOI:10.1038/s41467-025-56318-7
UR  - https://inrepo02.dkfz.de/record/298222
ER  -