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Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic

Sudipta Biswas1, Kai Kang1, Kwok Peng Ng1

  • 1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Cell Reports
|August 19, 2023
PubMed

Insights

Targeting DNA methyltransferase 1 (DNMT1) reactivates neuroendocrine lineage maturation in small cell lung cancer (SCLC). This approach offers a novel, non-cytotoxic therapy for chemo/ICI-refractory SCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Small cell lung cancer (SCLC) exhibits rapid resistance to chemotherapy and immune checkpoint inhibitors (ICIs).
  • SCLC cells undergo neuroendocrine lineage commitment and maturation arrest.
  • Novel therapeutic strategies are crucial for treating refractory SCLC.

Purpose of the Study:

  • To investigate the role of DNA methyltransferase 1 (DNMT1) in SCLC lineage commitment and maturation arrest.
  • To explore DNMT1 inhibition as a potential non-cross-resistant therapeutic strategy for SCLC.

Main Methods:

  • Analysis of DNA methylation patterns and gene expression in SCLC cells.
  • Assessment of DNMT1 amplification and Ten-Eleven-Translocation 2 (TET2) deletion.
  • Investigation of DNMT1 recruitment to transcription factor hubs (ASCL1, NEUROD1).
  • Evaluation of DNMT1 knockdown effects on SCLC cell cycling and lineage maturation.
  • Testing of DNMT1/corepressor inhibitors in mouse models of refractory SCLC.

Main Results:

  • DNMT1-mediated CpG methylation is retained at suppressed neuroendocrine genes during SCLC maturation arrest.
  • DNMT1 is amplified, while TET2 is deleted in SCLC, suggesting a dysregulated epigenetic landscape.
  • DNMT1 knockdown promotes SCLC cell cycle exit via terminal lineage maturation, independent of p53/apoptosis.
  • Inhibition of DNMT1/corepressors significantly extended survival in mice with disseminated, refractory SCLC.

Conclusions:

  • DNMT1 plays a critical role in maintaining SCLC lineage commitment and maturation arrest.
  • Targeting DNMT1 offers a promising non-cytotoxic therapeutic avenue for chemo-refractory and ICI-refractory SCLC.
  • Leveraging SCLC lineage commitment through DNMT1 inhibition represents a novel strategy against treatment-resistant lung cancer.
Keywords:
5-azacytidineCP: Cancerchemotherapy resistancedecitabineimmune checkpoint blockadepyrimidine metabolismradiation resistancesmall cell lung cancertetrahydrouridine

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