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. 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. 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.

中文翻译：

---

小细胞肺癌细胞系的表观基因组范围的 DNA 甲基化分析表明潜在的化疗靶点。

小细胞肺癌 (SCLC) 是一种侵袭性神经内分泌肺癌。SCLC 进展和治疗抵抗涉及表观遗传过程。然而，SCLC DNA 甲基化与药物反应之间的联系仍不清楚。我们使用 Illumina Infinium MethylationEPIC BeadChip 阵列对 66 个人类 SCLC 细胞系进行了表观基因组范围的研究。检查了 SCLC DNA 甲基化和基因表达与对 526 种抗肿瘤剂的体外反应的相关性。我们发现 DNA 甲基化与化学敏感性之间存在多种显着相关性。观察到 TREX1 存在潜在的重要关联，TREX1 编码 3' 外切核酸酶 I，在调节细胞溶质 DNA 传感途径中充当 STING 拮抗剂。TREX1 甲基化增加和低表达与对 Aurora 激酶抑制剂 AZD-1152、SCH-1473759、SNS-314 和 TAK-901 的敏感性有关；CDK抑制剂R-547；Vertex ATR 抑制剂 Cpd 45；和有丝分裂纺锤体干扰剂长春瑞滨。与其他癌症类型的细胞系相比，TREX1 在 SCLC 中具有低 mRNA 表达和增加的上游区域甲基化，表明可能与 SCLC 对 Aurora 激酶抑制剂的敏感性有关。我们还确定了指示化学敏感性潜在机制的多个额外相关性。CEP350 和 MLPH 的 3'UTR 甲基化分别参与中心体机制和微管追踪，与对 Aurora 激酶抑制剂和其他药物的反应有关。EPAS1 甲基化与对 Aurora 激酶抑制剂的反应有关，PLK-1 抑制剂和 Bcl-2 抑制剂。KDM1A 甲基化与 PLK-1 抑制剂和 KSP 抑制剂有关。由于 SLFN11 表达低或不表达，SLFN11 的启动子甲基化增加与对 DNA 损伤剂的抗性相关。表观遗传修饰符 EZH2 的 5' UTR 与对 Aurora 激酶抑制剂和 FGFR 抑制剂的反应有关。YAP1 的甲基化和表达与对 mTOR 抑制剂的反应相关。在非神经内分泌标记物中，EPHA2 与对 Aurora 激酶抑制剂和 PLK-1 抑制剂的反应以及 CD151 与 Bcl-2 抑制剂的反应有关。多重关联表明影响 SCLC 对化疗反应的潜在表观遗传机制，并建议联合治疗的目标。虽然许多相关性并非特定于 SCLC 谱系，