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

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.