Persister state-directed transitioning and vulnerability in melanoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Biology

Background:

• Melanoma exhibits high plasticity, with cells interconverting identities.
• High KDM5B (JARID1B) expression in melanoma cells induces a reversible, slow-cycling persister state.
• Understanding KDM5B-expressing melanoma cells is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To investigate the cellular identity of KDM5B-high persister melanoma cells.
• To identify chemical agents that can induce a similar state to KDM5B-high cells.
• To explore a potential dual-hit therapeutic strategy for melanoma.

Main Methods:

• Established a doxycycline-inducible system for KDM5B expression.
• Screened for chemical agents that phenocopy KDM5B-high expression.
• Utilized transcriptional profiling and cell functional assays.
• Investigated the effect of Cpd1 on melanoma cell differentiation and proliferation.

Main Results:

• Identified Cpd1, a dihydropyridine derivative, that robustly increases KDM5B expression.
• Cpd1 treatment induced melanoma cell differentiation along the melanocytic lineage and cell cycle arrest.
• The KDM5B-high state, induced by Cpd1, inhibits proliferation by regulating cytokinetic abscission.
• Cpd1 treatment enhanced melanoma cell sensitivity to the prodrug TMECG via tyrosinase expression.

Conclusions:

• Proof-of-concept for a dual-hit strategy targeting melanoma plasticity and cell elimination.
• Inducing differentiation and cell cycle arrest in melanoma persister cells limits tumor repopulation.
• Priming melanoma cells for lineage-specific elimination enhances therapeutic efficacy.