Inhibition of BIRC5 and MCL1 as a potential treatment strategy to overcome drug resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a difficult-to-cure, highly heterogeneous, and aggressive form of non-Hodgkin lymphoma with a high recurrence rate and poor long-term prognosis. Using a novel optimization-regularization-based computational prediction algorithm called “secDrug,” we have identified therapeutic targets for treating resistant cancers. When applied to B-cell malignancies, the secDrug algorithm predicted the pro-survival proteins BIRC5 and MCL1 as top targets. Here, using a panel of MCL cell lines representing PI/BTKi sensitive, innate resistance, and clonally derived acquired resistance, we demonstrated that small molecule-based inhibition of BIRC5 and MCL1 is effective in killing MCL cells as single agents and in combination with Bortezomib or Ibrutinib. Further, using bulk and single-cell transcriptomics, gene knockdown studies, and cell-based assays, we identified genes and molecular networks associated with their mechanism of action and synergy. In silico analysis using patient datasets underlined the clinical potential of these candidates in curbing MCL progression and drug resistance.