The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity

A large-scale integrated analysis of differentially methylated sites, genetic, epigenetic, and transcriptomic datasets identifies epigenetic drug response biomarkers across multiple cancer types. Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.

Automated summary

A comprehensive analysis of different types of cancer reveals epigenetic drug response biomarkers, including differentially methylated sites, genetic, epigenetic, and transcriptomic datasets. Aberrant DNA methylation is associated with genetic alterations and plays a role in cancer-related transcriptional deregulation. This study analyzes 721 cancer cell lines from 22 cancer types treated with 453 anti-cancer compounds, identifying 19 DNA methylation biomarkers across five cancer types and 17 drugs. DNA methylation acts as a predictive biomarker by regulating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Notably, the study also uncovers the potential sensitivity of melanoma to a specific inhibitor through NEK9 promoter hypermethylation-induced downregulation of NEK9. Overall, epigenomics has the potential to improve patient stratification and facilitate precision oncology.