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Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy
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 th...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528072/ https://www.ncbi.nlm.nih.gov/pubmed/37597186 http://dx.doi.org/10.1016/j.celrep.2023.113016 |
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author | Biswas, Sudipta Kang, Kai Ng, Kwok Peng Radivoyevitch, Tomas Schalper, Kurt Zhang, Hua Lindner, Daniel J. Thomas, Anish MacPherson, David Gastman, Brian Schrump, David S. Kwok-Kin, Wong Velcheti, Vamsidhar Saunthararajah, Yogen |
author_facet | Biswas, Sudipta Kang, Kai Ng, Kwok Peng Radivoyevitch, Tomas Schalper, Kurt Zhang, Hua Lindner, Daniel J. Thomas, Anish MacPherson, David Gastman, Brian Schrump, David S. Kwok-Kin, Wong Velcheti, Vamsidhar Saunthararajah, Yogen |
author_sort | Biswas, Sudipta |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10528072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
record_format | MEDLINE/PubMed |
spelling | pubmed-105280722023-09-27 Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy Biswas, Sudipta Kang, Kai Ng, Kwok Peng Radivoyevitch, Tomas Schalper, Kurt Zhang, Hua Lindner, Daniel J. Thomas, Anish MacPherson, David Gastman, Brian Schrump, David S. Kwok-Kin, Wong Velcheti, Vamsidhar Saunthararajah, Yogen Cell Rep Article 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. 2023-08-29 2023-08-18 /pmc/articles/PMC10528072/ /pubmed/37597186 http://dx.doi.org/10.1016/j.celrep.2023.113016 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Biswas, Sudipta Kang, Kai Ng, Kwok Peng Radivoyevitch, Tomas Schalper, Kurt Zhang, Hua Lindner, Daniel J. Thomas, Anish MacPherson, David Gastman, Brian Schrump, David S. Kwok-Kin, Wong Velcheti, Vamsidhar Saunthararajah, Yogen Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title | Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title_full | Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title_fullStr | Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title_full_unstemmed | Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title_short | Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
title_sort | neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528072/ https://www.ncbi.nlm.nih.gov/pubmed/37597186 http://dx.doi.org/10.1016/j.celrep.2023.113016 |
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