Aberrant expression of apoptosis-regulating Bcl-2 family members can promote malignant transformation and resistance to therapy. Notably, direct inhibition of Bcl-2 itself using the Bcl-2-specific antagonist ABT-199 (venetoclax) has already shown great promise for hematologic malignancies in the clinic. The Bcl-2-relative Mcl-1 is also deregulated in many blood cancers and hence is a promising therapeutic target.
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma that typically responds only transiently to chemotherapy. Although targeted therapies for MCL have now entered the clinic, new therapeutic approaches are still urgently needed. To establish whether Mcl-1 is critical for maintaining MCL cell survival, we first tested the impact of acute Mcl-1 knockout using an inducible CRISPR/Cas9 system. Intriguingly, induction of MCL1-sgRNA expression triggered spontaneous apoptosis in most MCL cell lines tested.
To further explore the potential of directly targeting Mcl-1 for treatment of MCL, we treated a panel of MCL cell lines with the new specific Mcl-1 inhibitor S63845. Four of five cell lines tested were very sensitive to the inhibitor, which strongly induced cell death. Furthermore, Mcl-1 inhibition showed synergy when combined with targeted therapies, such as the Bruton’s tyrosine kinase inhibitor ibrutinib or ABT-199.
To confirm these results in a more clinically relevant setting, we are testing the efficacy of the Mcl-1 inhibitor in primary samples from MCL patients, using CD40L-expressing feeder cells to mimic the microenvironment. Initial tests show sensitivity of primary MCL cells to S63845 alone and in combination. Although the microenvironment can modulate S63845 action, cell death can be restored by combination treatment strategies.
Together, our findings strongly suggest that Mcl-1 is crucial for maintenance of MCL. It represents a promising therapeutic target for this and related malignancies and might well circumvent their frequently observed resistance to current therapies.