{"doi":"10.1016/j.celrep.2023.113016","title":"Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy","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.","journal":"Cell Reports","year":2023,"id":352912,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1098794,"name":"Kai Kang","orcid":"0000-0001-7936-8569","position":1,"is_corresponding":false},{"id":1098795,"name":"Kwok Peng Ng","orcid":"0000-0003-1779-556X","position":2,"is_corresponding":false},{"id":278920,"name":"Tomas Radivoyevitch","orcid":"0000-0002-9701-1851","position":3,"is_corresponding":false},{"id":226310,"name":"Kurt A. Schalper","orcid":"0000-0001-5692-4833","position":4,"is_corresponding":false},{"id":1098796,"name":"Zhang Hua","orcid":"0000-0001-7704-4712","position":5,"is_corresponding":false},{"id":323647,"name":"Daniel J. Lindner","orcid":"0000-0002-8296-7703","position":6,"is_corresponding":false},{"id":253875,"name":"Anish Thomas","orcid":"0000-0003-3293-3115","position":7,"is_corresponding":false},{"id":251318,"name":"David MacPherson","orcid":"0000-0003-3729-907X","position":8,"is_corresponding":false},{"id":864584,"name":"Brian Gastman","orcid":"0000-0003-2691-3409","position":9,"is_corresponding":false},{"id":399102,"name":"David S. Schrump","orcid":"0000-0003-3613-1400","position":10,"is_corresponding":false},{"id":20939,"name":"Kwok‐Kin Wong","orcid":"0000-0001-6323-235X","position":11,"is_corresponding":false},{"id":264739,"name":"Vamsidhar Velcheti","orcid":"0000-0002-6589-0759","position":12,"is_corresponding":false},{"id":278926,"name":"Yogen Saunthararajah","orcid":"0000-0002-9757-1031","position":13,"is_corresponding":false},{"id":753220,"name":"Sudipta Biswas","orcid":"0000-0003-1235-364X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37597186","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}