Dual targeting of PI3K and BCL‐2 overcomes ibrutinib resistance in aggressive mantle cell lymphoma

Despite significant efficacy of ibrutinib therapy in mantle cell lymphoma (MCL), about one‐third of MCL patients will display primary resistance. In time, secondary resistance occurs almost universally with an unlikely response to salvage chemotherapy afterwards. While intense efforts are being directed towards the characterization of resistance mechanisms, our focus is on identifying the signalling network rewiring that characterizes this ibrutinib resistant phenotype. Importantly, intrinsic genetic, epigenetic and tumour microenvironment‐initiated mechanisms have all been shown to influence the occurrence of the ibrutinib resistant phenotype. By using in vitro and in vivo models of primary and secondary ibrutinib resistance as well as post‐ibrutinib treatment clinical samples, we show that dual targeting of the BCL‐2 and PI3‐kinase signalling pathways results in synergistic anti‐tumour activity. Clinically relevant doses of venetoclax, a BCL‐2 inhibitor, in combination with duvelisib, a PI3Kδ/γ dual inhibitor, resulted in significant inhibition of these compensatory pathways and apoptosis induction. Our preclinical results suggest that the combination of venetoclax and duvelisib may be a therapeutic option for MCL patients who experienced ibrutinib failure and merits careful consideration for future clinical trial evaluation.