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Bruton tyrosine kinase inhibitors (BTKi) have transformed the therapeutic landscape of B-cell lymphoma including the aggressive mantle cell lymphoma (MCL) subtype, although primary and acquired resistance is frequently observed. Interestingly, preliminary results have suggested that the second-generation, orally bioavailable and clinical-stage CDK4/6 inhibitor, ON123300 (narazaciclib), may be effective in preclinical models of BTKi-resistant MCL. We compared the efficacy and safety of ON123300 vs the approved CDK inhibitors palbociclib, abemaciclib or ribociclib, in association with various BTKi, in a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib, or the second generation acalabrutinib. We evaluated the effects of these combinations by CellTiter-Glo proliferation assay, FACS-mediated analysis of cell cycle and apoptosis, RT-PCR and western blot. Efficacy and safety of …