Precision medicine in oncology has made significant progress in recent years by approving drugs that target specific genetic mutations. However, many cancer driver genes remain challenging to pharmacologically target ("undruggable"). To tackle this issue, RNA-based methods like antisense oligonucleotides (ASOs) that induce targeted exon skipping (ES) could provide a promising alternative. In this work, a comprehensive computational procedure is presented, focused on the development of ES-based cancer treatments. The procedure aims to produce specific protein variants, including inactive oncogenes and partially restored tumor suppressors. This novel computational procedure encompasses target-exon selection, in silico prediction of ES products, and identification of the best candidate ASOs for further experimental validation. The method was effectively employed on extensively mutated cancer genes, prioritized according to their suitability for ES-based interventions. Notable genes, such as NRAS and VHL, exhibited potential for this therapeutic approach, as specific target exons were identified and optimal ASO sequences were devised to induce their skipping. To the best of our knowledge, this is the first computational procedure that encompasses all necessary steps for designing ASO sequences tailored for targeted ES, contributing with a versatile and innovative approach to addressing the challenges posed by undruggable cancer driver genes and beyond.
Keywords: ASO; RNA therapy; antisense oligonucleotide; bioinformatics; cancer; splicing; targeted exon skipping.