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

  • Cell Rep. 2023 Aug 18;42(8):113016. doi: 10.1016/j.celrep.2023.113016.
Sudipta Biswas  1 ,  Kai Kang  1 ,  Kwok Peng Ng  1 ,  Tomas Radivoyevitch  2 ,  Kurt Schalper  3 ,  Hua Zhang  4 ,  Daniel J Lindner  1 ,  Anish Thomas  5 ,  David MacPherson  6 ,  Brian Gastman  7 ,  David S Schrump  8 ,  Kwok-Kin Wong  4 ,  Vamsidhar Velcheti  9 ,  Yogen Saunthararajah  10
Affiliations
  • 1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 2. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 3. Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 4. Thoracic Oncology Program, Langone-Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY 10016, USA.
  • 5. Experimental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • 6. Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 7. Department of Plastic Surgery, Surgery Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 8. Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • 9. Thoracic Oncology Program, Langone-Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY 10016, USA. Electronic address: [email protected].
  • 10. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].
PMID: 37597186 DOI: 10.1016/j.celrep.2023.113016
Abstract

Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA Methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression MARK methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as Other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/Apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.

Keywords
5-azacytidine; CP: Cancer; chemotherapy resistance; decitabine; immune checkpoint blockade; pyrimidine metabolism; radiation resistance; small cell lung cancer; tetrahydrouridine.
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