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

Sep 24, 2026

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Small cell lung cancers rapidly develop resistance to cytotoxic chemotherapy and immune checkpoint inhibitor treatments, leaving limited options for chemo/ICI-refractory disease. The article investigates how SCLC neuroendocrine-lineage commitment becomes maturation-arrested and identifies DNA methyltransferase 1 (DNMT1) as a key regulator of this arrest. DNMT1 repression via methylated CpG persists at suppressed neuroendocrine genes, while DNMT1 amplification and TET2 deletion are observed. DNMT1 is recruited to ASCL1/NEUROD1 hubs; DNMT1 knockdown activates ASCL1 targets and induces lineage maturation-driven cell-cycle exit independent of p53/apoptosis. Clinical DNMT1/corepressor inhibition extends survival in mouse models with p53-null disseminated SCLC, enabling a noncytotoxic therapeutic strategy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages36

Reading Time1 h 31 min

AccessFree to download

SUMMARY

AUTHOR CONTRIBUTIONS

DECLARATION OF INTERESTS

SUPPLEMENTAL INFORMATION

INTRODUCTION

Need for non-cross-resistant therapies

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Cell Rep. Author manuscript; available in PMC 2023 September 27. | | --- | --- | Published in final edited form as: Cell Rep. 2023 August 29; 42(8): 113016. doi:10.1016/j.celrep.2023.113016 . Neuroendocrine lineage commitment of small cell lung cancerscan be leveraged into p53-independent non-cytotoxic therapy Sudipta Biswas 1 , Kai Kang 1 , Kwok Peng Ng 1 , Tomas Radivoyevitch2 , Kurt Schalper3 , Hua Zhang4 , Daniel J. Lindner1 , Anish Thomas5 , David MacPherson6 , Brian Gastman7 , David S. Schrump8 , Wong Kwok-Kin4 , Vamsidhar Velcheti4,* , Yogen Saunthararajah 1,9,10,* 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 4Thoracic 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 8Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA 9 Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA 10Lead contact SUMMARY This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). *[Correspondence: vamsidhar.velcheti@nyulangone.org](Correspondence: vamsidhar.velcheti@nyulangone.org) (V.V.), [saunthy@ccf.org](saunthy@ccf.org) (Y. S.) . AUTHOR CONTRIBUTIONS Conception and design: Y.S. and V.V.; development of methodology: Y.S., V.V., S.B., K.K., and D.J.L.; acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Y.S., V.V., S.B., K.K., K.P.N., D.J.L., and D.M.; analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Y.S., V.V., S.B., K.K., and T.R.; writing, review, and/or revision of the manuscript: Y.S., V.V., S.B., K.K., T.R., K.S., D.J.L., A.T., D.M., D.S.S., and K.-K.W.; administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Y.S., V.V., S.B., K.K., T.R., B.G., K.S., D.J.L., H.Z., A.T., D.M., D.S.S., and K.-K.W.; study supervision: Y.S. and V.V. DECLARATION OF INTERESTS Ownership: Y.S., EpiDestiny. Consultancy: K.S., Merck, Takeda Pharmaceuticals, Shattuck Labs, Pierre-Fabre, and Celgene; Y.S., EpiDestiny; V.V., Bristol Myers, AstraZeneca, Genentech, Merck, Taekeda, Reddy Labs, Celgene, Foundation Medicine, Nektar Therapeutics, Alkermes, and Amgen. Research support: V.V., Genentech, Alkermes, BMS, Merck, Esai, Navigate Biopharma, Leap Therapeutics, and AstraZeneca; K.S., Vasculox/Tioma, Navigate Biopharma, Tesaro Inc., Onkaido Therapeutics/Moderna, Takeda Pharmaceuticals, Surface Oncology, Pierre-Fabre, Merck, and Bristol-Myers Squibb. Intellectual property: Y.S., patents around tetrahydrouridine, decitabine, and 5-azacytidine (US 9,259,469 B2, US 9,265,785 B2, and US 9,895,391 B2) . SUPPLEMENTAL INFORMATION Supplemental information can be found online at [https://doi.org/10.1016/j.celrep.2023.113016](https://doi.org/10.1016/j.celrep.2023.113016) . Author Manuscript Author Manuscript Author Manuscript Author Manuscript Biswas et al. Page 2 Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus

FAQs

Why are new therapies needed for small cell lung cancer?

SCLC rapidly resists standard cytotoxic chemotherapy and immune checkpoint inhibitor treatments, especially in disseminated and chemo/ICI-refractory settings.

What role does DNMT1 play in neuroendocrine-lineage commitment and maturation arrest?

The study links DNMT1-mediated methylation to the retention of repression at suppressed neuroendocrine-lineage genes and to DNMT1 recruitment at ASCL1/NEUROD1 master transcription factor hubs.

How does targeting DNMT1 enable a p53-independent non-cytotoxic approach?

DNMT1 knockdown activates ASCL1-target genes and drives lineage-maturation-associated cell-cycle exits without requiring the p53/apoptosis pathway used by cytotoxic chemotherapy; DNMT1/corepressor inhibition extends survival in p53-null disseminated SCLC mice.

Sep 24, 2026

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