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@ARTICLE{Arseni:298222,
author = {L. Arseni$^*$ and G. Sigismondo$^*$ and H. Yazdanparast$^*$
and J. U. Hermansen and N. Mack$^*$ and S. Ohl$^*$ and V.
Kalter$^*$ and M. Iskar$^*$ and M. Kalxdorf and D.
Friedel$^*$ and M. Rettel and Y. Paul$^*$ and I. Ringshausen
and E. Eldering and J. Dubois and A. P. Kater and M.
Zapatka$^*$ and P. M. Roessner$^*$ and E. Tausch and S.
Stilgenbauer and S. Dietrich and M. M. Savitski and S. S.
Skånland and J. Krijgsveld$^*$ and P. Lichter$^*$ and M.
Seiffert$^*$},
title = {{L}ongitudinal omics data and preclinical treatment suggest
the proteasome inhibitor carfilzomib as therapy for
ibrutinib-resistant {CLL}.},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DKFZ-2025-00229},
pages = {1041},
year = {2025},
note = {#EA:B060#EA:B230#LA:B060#},
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.},
keywords = {Adenine: analogs $\&$ derivatives / Adenine: therapeutic
use / Adenine: pharmacology / Leukemia, Lymphocytic,
Chronic, B-Cell: drug therapy / Leukemia, Lymphocytic,
Chronic, B-Cell: genetics / Leukemia, Lymphocytic, Chronic,
B-Cell: metabolism / Piperidines: pharmacology /
Piperidines: therapeutic use / Animals / Humans / Proteasome
Inhibitors: pharmacology / Proteasome Inhibitors:
therapeutic use / Drug Resistance, Neoplasm: genetics / Drug
Resistance, Neoplasm: drug effects / Oligopeptides:
pharmacology / Oligopeptides: therapeutic use / Mice /
Pyrimidines: pharmacology / Pyrimidines: therapeutic use /
Pyrazoles: pharmacology / Pyrazoles: therapeutic use /
Proteomics / Proteasome Endopeptidase Complex: metabolism /
Disease Models, Animal / Female / Cell Line, Tumor /
ibrutinib (NLM Chemicals) / carfilzomib (NLM Chemicals) /
Adenine (NLM Chemicals) / Piperidines (NLM Chemicals) /
Proteasome Inhibitors (NLM Chemicals) / Oligopeptides (NLM
Chemicals) / Pyrimidines (NLM Chemicals) / Pyrazoles (NLM
Chemicals) / Proteasome Endopeptidase Complex (NLM
Chemicals)},
cin = {B060 / B230 / B300},
ddc = {500},
cid = {I:(DE-He78)B060-20160331 / I:(DE-He78)B230-20160331 /
I:(DE-He78)B300-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39863584},
pmc = {pmc:PMC11762753},
doi = {10.1038/s41467-025-56318-7},
url = {https://inrepo02.dkfz.de/record/298222},
}