Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with limited treatment advancements.
• Few actionable mutations exist in SCLC, unlike non-small cell lung cancer (NSCLC).
• The mechanism of action for Lysine-specific histone demethylase 1A (LSD1) inhibitors in SCLC was previously unclear.

Purpose of the Study:

• To elucidate the mechanism by which LSD1 inhibitors exert selective activity in SCLC.
• To investigate the role of the NOTCH pathway in LSD1 inhibitor-mediated SCLC suppression.
• To evaluate the therapeutic potential of LSD1 inhibition in SCLC models.

Main Methods:

• Treatment of SCLC models with the selective LSD1 inhibitor ORY-1001.
• Analysis of NOTCH pathway activation, ASCL1 expression, and neuroendocrine gene regulation.
• Confirmation using knockdown studies and evaluation in patient-derived xenograft (PDX) models.

Main Results:

• ORY-1001 activated the NOTCH pathway, suppressing SCLC tumorigenesis by inhibiting ASCL1.
• LSD1 was found to bind the NOTCH1 locus, repressing NOTCH1 expression and signaling.
• Sensitivity to LSD1 inhibition correlated with NOTCH pathway activation and neuroendocrine phenotype repression in PDX models.
• Complete and durable tumor regression was observed in a chemoresistant PDX model with ORY-1001 treatment.

Conclusions:

• LSD1 inhibition reactivates NOTCH signaling, suppressing SCLC growth by reducing ASCL1 and neuroendocrine gene expression.
• LSD1 inhibitors represent a potential new targeted therapy for SCLC.
• The findings provide mechanistic insight into LSD1 inhibitor efficacy in SCLC.