Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy [RNA-seq]
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. Overall design: Objectives were to evaluate the potential of non-cytotoxic DNMT1-targeting using decitabine and 5-azacytidine to treat chemorefractory SCLC. The central hypothesis was that DNMT1-depletion from SCLC cells would release cell cycle exits by terminal-maturation, a pathway not cross-resistant with the p53/apoptosis pathway utilized by chemo-radiation.