Loss of SNORD104-guided rRNA methylation promotes early adaptation to crizotinib in lung adenocarcinoma

Abstract

The ribosome, long considered an invariant actor of gene expression, recently emerged as a contributor to translational control through chemical modifications of ribosomal RNAs (rRNAs). These modifications are guided by small nucleolar RNAs (snoRNAs), which direct modifying enzymes to specific rRNA positions. Here, we report that lung adenocarcinoma (LUAD) cells that are resistant to tyrosine kinase inhibitors (TKIs) reshape both their translational program and rRNA 2’O-ribose methylation (2’Ome) profiles. EML4-ALK -positive LUAD cells that are resistant to crizotinib (ALK inhibitor) exhibit reduced global protein synthesis and a change in selective translation of mRNAs, encoding proteins previously linked to resistance. These cells show concomitant reduction in SNORD104 and 2’Ome at its associated 28S_Cm1327 position. Functional studies reveal that SNORD104 depletion abolishes 2’Ome at 28S_Cm1327 without affecting basal translation or cell viability, but enhances both under crizotinib exposure. Moreover, SNORD104 knockdown attenuates caspase activation and PARP cleavage during treatment, supporting reduced cell death. Altogether, our findings support a role for snoRNA-guided rRNA modification as a novel non-genomic mechanism in early adaptive responses to crizotinib therapy in LUAD.