Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy
Sudipta Biswas,
Kai Kang,
Kwok Peng Ng,
Tomas Radivoyevitch,
Kurt Schalper,
Hua Zhang,
Daniel J. Lindner,
Anish Thomas,
David MacPherson,
Brian Gastman,
David S. Schrump,
Kwok-Kin Wong,
Vamsidhar Velcheti,
Yogen Saunthararajah
Affiliations
Sudipta Biswas
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Kai Kang
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Kwok Peng Ng
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Tomas Radivoyevitch
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA
Kurt Schalper
Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA
Hua Zhang
Thoracic Oncology Program, Langone-Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY 10016, USA
Daniel J. Lindner
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Anish Thomas
Experimental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
David MacPherson
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Brian Gastman
Department of Plastic Surgery, Surgery Institute, Cleveland Clinic, Cleveland, OH 44195, USA
David S. Schrump
Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Kwok-Kin Wong
Thoracic Oncology Program, Langone-Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY 10016, USA
Vamsidhar Velcheti
Thoracic Oncology Program, Langone-Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY 10016, USA; Corresponding author
Yogen Saunthararajah
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; Corresponding author
Summary: 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.
