Associating lncRNAs with small molecules via bilevel optimization reveals cancer-related lncRNAs

Long noncoding RNA (lncRNA) transcripts have emerging impacts in cancer studies, which suggests their potential as novel therapeutic agents. However, the molecular mechanism behind their treatment effects is still unclear. Here, we designed a computational model to Associate LncRNAs with Anti-Cancer Drugs (ALACD) based on a bilevel optimization model, which optimized the gene signature overlap in the upper level and imputed the missing lncRNA-gene association in the lower level. ALACD predicts genes coexpressed with lncRNAs mean while matching drug’s gene signatures. This model allows us to borrow the target gene information of small molecules to understand the mechanisms of action of lncRNAs and their roles in cancer. The ALACD model was systematically applied to the 10 cancer types in The Cancer Genome Atlas (TCGA) that had matched lncRNA and mRNA expression data. Cancer type-specific lncRNAs and associated drugs were identified. These lncRNAs show significantly different expression levels in cancer patients. Follow-up functional and molecular pathway analysis suggest the gene signatures bridging drugs and lncRNAs are closely related to cancer development. Importantly, patient survival information and evidence from the literature suggest that the lncRNAs and drug-lncRNA associations identified by the ALACD model can provide an alternative choice for cancer targeting treatment and potential cancer pognostic biomarkers. The ALACD model is freely available at https://github.com/wangyc82/ALACD-v1.Author summary: LncRNAs are RNA transcripts that are longer than 200 bp and do not encode proteins. Recent experimental studies have indicated the crucial role of lncRNAs in cancer. We proposed a computational model, ALACD, to understand a lncRNA’s molecular mechanism by associating it with a drug through the drug’s target genes. ALACD reveals lncRNAs, the associated anti-cancer drug, and the induced gene signatures that are involved in the regulation of cancer. Furthermore, these cancer-related lncRNAs are differentially expressed in cancer patients and closely associated with patient survival.