LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Area of Science:

• Oncology
• Epigenetics
• Dermatology

Background:

• Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer lacking actionable mutations for targeted therapy.
• Epigenetic regulators controlling cell identity present potential therapeutic targets.

Purpose of the Study:

• To identify and evaluate epigenetic regulators as therapeutic targets in MCC.
• To investigate the role of lysine-specific histone demethylase 1A (LSD1/KDM1A) in MCC proliferation and identify its downstream effectors.

Main Methods:

• Pharmacological screening of epigenetic regulators.
• In vitro and in vivo studies of MCC cell lines and tumors.
• Analysis of LSD1-CoREST complex, HMG20B levels, gene expression, and cell cycle.
• Assessment of combination therapy with checkpoint inhibitors.

Main Results:

• LSD1/KDM1A was identified as essential for MCC growth.
• LSD1 inhibition disrupted the LSD1-CoREST complex, leading to HMG20B degradation and impaired MCC proliferation.
• LSD1 inhibition reactivated neuronal lineage regulators, induced a Merkel cell gene signature, and triggered cell cycle arrest and death.
• LSD1 inhibition showed potential in combination with checkpoint inhibitors.

Conclusions:

• LSD1 is crucial for maintaining MCC cellular plasticity and proliferation.
• Targeting LSD1 represents a promising therapeutic strategy for MCC.
• Combining LSD1 inhibitors with immune checkpoint inhibitors may enhance treatment efficacy for MCC patients.