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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 for  TREX1 , 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 of  TREX1  were 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,  TREX1  had 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 of  CEP350  and  MLPH , involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents.  EPAS1  methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor.  KDM1A  methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of  SLFN11  was correlated with resistance to DNA damaging agents, as a result of low or no  SLFN11  expression. The 5′ UTR of the epigenetic modifier  EZH2  was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of  YAP1  were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers,  EPHA2  was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and  CD151  with 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.

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