Longitudinal omics data and preclinical treatment identify proteasome inhibition as therapy for ibrutinib-resistant CLL

ABSTRACT: Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been fully elucidated yet. To overcome this limitation, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive salvage treatment option for CLL patients resistant or refractory to ibrutinib.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): B Cell

DISEASE(S): Chronic Lymphocytic Leukemia

SUBMITTER: Gianluca Sigismondo  

LAB HEAD: Martina Seiffert

PROVIDER: PXD053512 | Pride | 2024-12-10

REPOSITORIES: Pride