2. Academic Validation
  3. Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy

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

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: vamsidhar.velcheti@nyulangone.org.
  • 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: saunthy@ccf.org.
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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