Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition

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

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.


Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001–induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.

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