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 emerges as regulated by chemical modifications of ribosomal RNAs (rRNAs). These modifications are guided by small nucleolar RNAs (snoRNAs), which direct enzymes to specific rRNA sites. Here, we reported that lung adenocarcinoma (LUAD) cells resistant to tyrosine kinase inhibitors (TKIs) reshape both their translational program and rRNA 2’O-ribose methylation (2’Ome) landscape. Crizotinib-resistant cells exhibit a reduced global protein synthesis and change in selective mRNA translation linked to known resistant pathways. These cells show concomitant reduction in SNORD104 and 2’Ome at its associated 28S_Cm1327 site. 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 TKI therapy in LUAD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317815 | GEO | 2026/08/28

REPOSITORIES: GEO