Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

Abstract

ABSTRACTDespite the growing interest in pre-mRNA alternative splicing (AS) as a therapeutic anticancer target, the potential of splicing inhibitors in treating solid tumors remains largely unexplored. We conducted a meta-analysis of transcriptome data from six different tumor types and revealed that splicing inhibitors induced similar patterns of AS, resulting in widespread exon-skipping and intron retention events that often lead to nonsense-mediated decay of the transcripts. Interestingly, in many cases exon skipping is induced by a compensatory cellular response to splicing inhibitor treatment. It involves an upregulation of multiple splicing factors and incomplete recognition of branch points by U2 snRNP. These post transcriptional changes downregulate one-third of essential DNA repair genes, thereby creating a therapeutic vulnerability that can be exploited for cancer treatment. To harness this vulnerability, we proposed a new approach to cancer treatment consisting of sequential addition of a splicing inhibitors followed by a DNA-damaging agent. Ourin vitroandin vivoexperiments demonstrated that this strategy exhibits promising therapeutic potential for a wide range of tumors.