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

  1. Author:
    Krushkal, Julia [ORCID]
    Silvers,Thomas
    Reinhold, William C
    Sonkin, Dmitriy
    Vural, Suleyman
    Connelly, John
    Varma, Sudhir
    Meltzer, Paul S
    Kunkel, Mark
    Rapisarda,Annamaria
    Evans, David
    Pommier, Yves
    Teicher, Beverly A
  2. Author Address

    Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, 9609 Medical Center Dr., Rockville, MD, 20850, USA. julia.krushkal@nih.gov., Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA., Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA., Drug Synthesis and Chemistry Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA., Molecular Pharmacology Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA. Beverly.Teicher@nih.gov.,
    1. Year: 2020
    2. Date: Jun 25
    3. Epub Date: 2020 06 25
  1. Journal: Clinical epigenetics
    1. 12
    2. 1
    3. Pages: 93
  2. Type of Article: Article
  3. Article Number: 93
  4. ISSN: 1868-7075
  1. Abstract:

    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.

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External Sources

  1. DOI: 10.1186/s13148-020-00876-8
  2. PMID: 32586373
  3. WOS: 000545585500001
  4. PII : 10.1186/s13148-020-00876-8

Library Notes

  1. Fiscal Year: FY2019-2020
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