Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors
Anufrieva, K. S.; Lukina, M. M.; Ivanova, O. M.; Kazakova, A. N.; Shnaider, P. V.; Klimina, K. M.; Veselovsky, V. A.; Luzhin, A. V.; Velichko, A. K.; Kantidze, O. L.; Mochalova, E. N.; Nikitin, M. P.; Kashina, A. V.; Vasilchikova, E. A.; Deev, R. V.; Emelin, A. M.; Turchin, A. N.; Liu, Z.; Wang, Z.; Boichenko, V. S.; Markina, N. M.; Lagarkova, M. A.; Govorun, V. M.; Arapidi, G. P.; Shender, V. O.
Show abstract
Despite 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. Our in vitro and in vivo experiments demonstrated that this strategy exhibits promising therapeutic potential for a wide range of tumors.
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