Publication in Nature Communications: Preclinical study suggests proteasome inhibitor as therapy for ibrutinib-resistant chronic lymphocytic leukemia
Drug resistance remains a major challenge in chronic lymphocytic leukemia (CLL). A study led by Martina Seiffert (German Cancer Research Center) in collaboration with Sigrid S. Skånland (Institute for Cancer Research) suggests that alterations in the proteasome activity drive resistance to the BTK inhibitor ibrutinib, and that proteasome inhibitors are effective in ibrutinib resistant or refractory CLL.
Treatment with ibrutinib can induce remissions for several years, yet development of drug resistance represents a major challenge. Mutations in BTK and the downstream protein PLCG2 are commonly detected in resistant disease, while mechanisms of resistance that are not explained by these mutations have not yet been understood.
In the Nature Communications article, a CLL mouse model of ibrutinib resistance was generated, and comparative omics analyses were performed to characterize the underlying mechanisms. The results suggested proteasome activity as a vulnerable target in the model. Treatment of the mice with a proteasome inhibitor prolonged survival. Proteome and ex vivo studies with primary human CLL cells verified the relevance of these findings for patients with ibrutinib-resistant CLL.
“This study supports our earlier findings which formed the basis for opening a CLL cohort in the IMPRESS-Norway clinical trial. Patients enrolled in this cohort will be treated with a proteasome inhibitor if their cancer cells show ex vivo sensitivity to the drug”, says Skånland.
Proteasome inhibitors are not approved for treatment of CLL, but are approved for other hematologic malignancies, mantle cell lymphoma and multiple myeloma.
Johanne U. Hermansen, PhD fellow in Skånland’s group, is a co-author on the publication.
LINKS:
The Nature Communications publication:
Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.
Arseni L, Sigismondo G, Yazdanparast H, Hermansen JU, Mack N, Ohl S, Kalter V, Iskar M, Kalxdorf M, Friedel D, Rettel M, Paul Y, Ringshausen I, Eldering E, Dubois J, Kater AP, Zapatka M, Roessner PM, Tausch E, Stilgenbauer S, Dietrich S, Savitski MM, Skånland SS, Krijgsveld J, Lichter P, Seiffert M.
Nat Commun. 2025 Jan 26;16(1):1041. doi: 10.1038/s41467-025-56318-7.
PMID: 39863584
Patient case with proteasome inhibitor (haematologica.org)
IMPRESS-Norway: (clinicaltrials.gov)
Sigrid Skånland’s project group