Differential Splicing of Skipped Exons Predicts Drug Response in Cancer Cell Lines

Abstract

Alternative splicing of pre-mRNA transcripts is an important regulatory mechanism that increases the diversity of gene products in eukaryotes. Various studies have linked specific transcript isoforms to altered drug response in cancer; however, few algorithms have incorporated splicing information into drug response prediction. In this study, we evaluated whether basal-level splicing information could be used to predict drug sensitivity by constructing doxorubicin-sensitivity classification models with splicing and expression data. We detailed splicing differences between sensitive and resistant cell lines by implementing quasi-binomial generalized linear modeling (QBGLM) and found altered inclusion of 277 skipped exons. We additionally conducted RNA-binding protein (RBP) binding motif enrichment and differential expression analysis to characterize cis- and trans-acting elements that potentially influence doxorubicin response-mediating splicing alterations. Our results showed that a classification model built with skipped exon data exhibited strong predictive power. We discovered an association between differentially spliced events and epithelial-mesenchymal transition (EMT) and observed motif enrichment, as well as differential expression of RBFOX and ELAVL RBP family members. Our work demonstrates the potential of incorporating splicing data into drug response algorithms and the utility of a QBGLM approach for fast, scalable identification of relevant splicing differences between large groups of samples.