Apoptosis-regulating BCL-2 family members, which can promote malignant transformation and resistance to
therapy, have become prime therapeutic targets, as illustrated by the striking efficacy in certain lymphoid
malignancies of the BCL-2-specific inhibitor
venetoclax. In other lymphoid
malignancies, however, such as the aggressive
mantle cell lymphoma (MCL), cell survival might rely instead or also on BCL-2 relative MCL-1. We have explored MCL-1 as a target for killing MCL cells by both genetic and pharmacologic approaches. In several MCL cell lines, MCL-1 knockout with an inducible CRISPR/Cas9 system triggered spontaneous apoptosis. Accordingly, most MCL cell lines proved sensitive to the specific MCL-1 inhibitor
S63845, and MCL-1 inhibition also proved efficacious in an MCL xenograft model. Furthermore, its killing efficacy rose on combination with
venetoclax, the BCL-XL-specific inhibitor
A-1331852, or
Bruton's tyrosine kinase (BTK) inhibitor
ibrutinib, which reduced pro-survival signals. We also tested the MCL-1 inhibitor in primary samples from 13 MCL patients, using CD40L-expressing feeder cells to model their microenvironmental support. Notably, all unstimulated primary MCL samples were very sensitive to
S63845, but the
CD40L stimulation attenuated their sensitivity. Mass cytometric analysis revealed that the stimulation likely conveyed protection by elevating BCL-XL and MCL-1. Accordingly, sensitivity of the CD40L-stimulated cells to
S63845 was substantially restored by co-treatment with
venetoclax, the BCL-XL-specific inhibitor or
ibrutinib. Overall, our findings indicate that MCL-1 is very important for survival of MCL cells and that the MCL-1 inhibitor, both alone and together with
ibrutinib,
venetoclax or a BCL-XL inhibitor, offers promise for novel improved MCL
therapies.