Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for treatment of hematological malignancies.We here evaluated the expression of several spliceosome machinery components in primary multiple myeloma (MM) cells and the impact of splicing modulations on MM cell growth and viability.Our comprehensive gene expression analysis confirmed deregulation of spliceosome machinery components in MM cells compared to normal plasma cells (PCs) from healthy donors, while pharmacological and genetic modulation of splicing confirmed significant impact on growth and survival of MM cell lines and patient-derived malignant PCs. Transcriptomic analysis revealed deregulation of BCL2 family membersincluding decrease of proapoptotic long form of myeloid cell leukemia-1 (MCL1) expression in cells treated with splicing inhibitors. This caused a shift in the apoptotic priming resulting in improved BCL2-dependenceand increased sensitivity to Venetoclax, a BCL2 small molecule inhibitor, in vitro and in vivo. Overall, our data provide a rationale for supporting clinical use of splicing modulators as strategy to reprogram apoptotic dependencies, making MM patients more vulnerable to BCL2 inhibitors.