Panel-Wide Screening of Tumour Cells of Diverse Histogenesis for Responsiveness to Silencing of miR-21, miR-17, and miR-155 by Mesyl Phosphoramidate Antisense Oligonucleotides

Molecular heterogeneity of malignant tumours remains a central challenge in oncology. Although neoplasms of distinct histogenesis share core oncogenic properties, the signalling networks sustaining these phenotypes are tumour-specific, highlighting the need for regulatory-level therapeutics adaptable to distinct molecular contexts. Oncogenic microRNAs (miRNAs), among which miR-21, miR-17, and miR-155 are broadly overexpressed in epithelial, lymphoid, and glial-neuronal neoplasms, represent attractive targets for therapeutic intervention. MiRNA inhibition by antisense oligonucleotides has emerged as a promising therapeutic strategy, and mesyl (methanesulfonyl) phosphoramidate oligonucleotides (µ-AMOs) represent a next-generation class of anti-miRNA agents with superior nuclease resistance and biological activity. Here, we report a systematic screening of 23 tumour cell lines of diverse histogenesis for sensitivity to paired combinations of µ-AMOs targeting miR-21, miR-17, and miR-155. Epithelial-derived lines exhibited the highest responsiveness, while lymphoid cell lines demonstrated the lowest sensitivity. The efficacy of specific µ-AMO pairs was found to be cell type-specific: combinations containing miR-21-targeting µ-AMO were most effective in epithelial lines, whereas the miR-17/miR-155-targeting pair showed superior activity in neuroglial models. Cellular responsiveness was driven by the extent of miRNA suppression, with no correlation detected for delivery efficiency or basal miRNA levels. The obtained results provide a basis for tumour-type-specific selection of µ-AMO combinations for clinical translation.