Inhibition of BIRC5 and MCL-1 as a potential treatment strategy to overcome drug resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a highly heterogeneous and aggressive form of non-Hodgkin lymphoma that develops from malignant B-lymphocytes in the outer edge (mantle zone) of lymph nodes [ 1 ]. Despite promising initial responses to conventional chemotherapeutic drugs and targeted therapies like Bruton’s tyrosine kinase inhibitor (BTKi) and proteasome inhibitors (PI), patients develop resistance over time, thus progressing into more aggressive, incurable, refractory or relapsed (R/R) disease states, with a median progression-free survival of ~15 months [ 1 ]. We have designed a novel pharmacogenomics data-driven computational pipeline that utilizes a modified greedy algorithm (minimal set-cover optimization followed by regularization) to predict molecular targets for the development of small-molecule inhibitors as secondary drug candidates (‘secDrugs’) for the management of treatment-resistant cancers [ 2 ]. Previously, we demonstrated that the top-predicted secDrugs show significant cytotoxicity against in vitro and ex vivo models of advanced-stage cancers, including relapsed/resistant multiple myeloma and lethal variants of prostate cancer [ 2 , 3 ]. Since the top among the predicted secDrug targets in drug-resistant B-cell malignancies included BIRC5 and MCL-1, we hypothesize that drug combinations utilizing BIRC5-inhibition and/or MCL-1-inhibition will be useful in curbing oncogenic progressions of MCL and abrogating drug resistance through simultaneous inhibition of multiple pathways [ 2 ]. Therefore, we selected YM155 (BIRC5 inhibitor) and S63845 (MCL-1 inhibitor) for our proof-of-concept experiments in MCL.