Work

Dual Proteasome and Histone Deacetylase Inhibition Overcomes Tyrosine Kinase Inhibitor Resistance in Breakpoint Cluster Region: Abelson 1‐Driven Leukaemia Cell Lines

Year: 2026

Type: article

Abstract: Resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge in breakpoint cluster region (BCR)::Abelson 1 (ABL1)-driven leukaemias. Asciminib offers a novel therapeutic option; however, resistance continues to emerge. We hypothesised that targeting proteostasis and epigenetic regulation with bortezomib and panobinostat could eliminate TKI-refractory cells via TKI-independent mechanisms. We profiled parental and TKI-resistant chronic myelogenous leukaemia (CML) and Ba/F3 models. Viability, cytotoxicity, and caspase-3/7 activity were assessed following single-agent treatment with asciminib, ponatinib, bortezomib, or panobinostat. The effects of the bortezomib-panobinostat combination on colony formation, mitochondrial membrane potential, and apoptosis were evaluated. Asciminib showed reduced potency in resistant models and a right-shifted dose-response curve in T315I cells, whereas ponatinib retained activity across BCR::ABL1 variants. Bortezomib and panobinostat induced low-nanomolar cytotoxicity and robust caspase-3/7 activation in resistant lines. The combination of bortezomib and panobinostat showed modest trends toward reduced cell viability and increased cytotoxicity and caspase-3/7 activity, especially in TKI-resistant cells. The combination suppressed clonogenic growth and triggered apoptosis in resistant cells. Co-inhibition of proteasomes and histone deacetylases eliminates TKI-refractory BCR::ABL1-driven leukaemia cells by inducing mitochondrial apoptosis and loss of clonogenic potential. These findings indicate a clinically actionable, TKI-independent strategy for the salvage treatment of multidrug-resistant CML.

Source: Journal of Cellular and Molecular Medicine

DOI: 10.1111/jcmm.71053

Authors: Seiichi Okabe, Seiichiro Yoshizawa, Yuya Arai, Akihiko Gotoh, Daigo Akahane

Institution: Tokyo Medical University

Language: English

Topic: Chronic Myeloid Leukemia Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,210