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

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 RNAseq (transcriptomics) and funcional genomics, we identified genes and molecular networks associated with their mechanism of action and synergy.