Transcriptome-wide RNA Stability Across Cancers Reveals Therapeutic Vulnerabilities.

The steady-state abundance of mRNA is governed by the interplay between transcription and degradation, yet the contribution of RNA stability to cancer biology remains incompletely understood. Here, we systematically investigate RNA decay dynamics across 22 cancer types using RNA-seq data from the Cancer Cell Line Encyclopedia. By inferring transcriptome-wide RNA stability profiles, we identify distinct molecular subtypes defined by post-transcriptional regulation. Integrative analyses reveal that RNA-binding proteins (RBPs) and microRNAs (miRNAs), including SNRPA and RBMX, act as key modulators of RNA stability and are essential for cancer cell proliferation and survival. Somatic mutations, particularly those affecting miRNA binding sites, were found to significantly perturb RNA decay, implicating dysregulation of pathways such as nonsense-mediated decay. Furthermore, machine learning models demonstrate that RNA stability profiles predict sensitivity to 24 anticancer drugs, nominating specific RBPs as candidate biomarkers for therapeutic response. Collectively, our findings establish RNA stability as a pivotal layer of gene regulation in cancer, with broad implications for molecular stratification and precision oncology.