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Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy [CUT&Tag]

ABSTRACT: Small cell lung cancers (SCLC) 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. The corepressor DNA methyltransferase 1 (DNMT1) mediates the maturation-arrests: (i) the repression mark methylated-CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (ii) DNMT1 is recurrently amplified, while Ten-Eleven-Translocation 2 (TET2) that functionally opposes DNMT1 is deleted; (iii) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (iv) DNMT1 knock-down activated ASCL1-target genes and released SCLC cell cycling exits by terminal lineage-maturation, 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 chemo- and ICI-refractory disseminated SCLC. Neuroendocrine-lineage commitment of SCLC cells can thus be leveraged into p53/apoptosis-independent therapy, active against chemo- and ICI-refractory SCLC.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE238003 | GEO | 2023/07/25

REPOSITORIES: GEO

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Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy [RNA-seq]

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