Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

Background Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. Results We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed forTREX1, which encodes the 3 ' exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression ofTREX1were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types,TREX1had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3 ' UTR ofCEP350andMLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents.EPAS1methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor.KDM1Amethylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation ofSLFN11was correlated with resistance to DNA damaging agents, as a result of low or noSLFN11expression. The 5 ' UTR of the epigenetic modifierEZH2was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression ofYAP1were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers,EPHA2was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor andCD151with Bcl-2 inhibitors. Conclusions Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.