Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition

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Sci. Signal.  05 Feb 2019:
Vol. 12, Issue 567, eaau2922
DOI: 10.1126/scisignal.aau2922

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Targeted epigenetic therapy for SCLC

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with no targeted therapeutic options and in which chemotherapy is only partially effective. Previous studies indicated that SCLC growth is suppressed by drugs that inhibit the histone lysine demethylase LSD1. Augert et al. found that LSD1 epigenetically suppressed the expression of the gene encoding NOTCH1, enabling the activity of the neuroendocrine cell lineage–associated transcription factor ASCL1. Blocking LSD1 with iadademstat (ORY-1001), a drug that has just been approved for phase 2 clinical trials in leukemia, reactivated NOTCH signaling and suppressed ASCL1 activity, inhibiting tumor growth and even inducing complete tumor regression in a patient-derived mouse model of SCLC.