Druggable dependency on histone demethylase LSD1 in MITF-low therapy resistant melanoma

Acquired and intrinsic resistance to targeted and immune therapies in melanoma is associated with an undifferentiated, mesenchymal-like tumor cell state characterized by low expression of the melanocytic lineage regulator MITF and high expression of the receptor tyrosine kinase AXL. Because MITF governs lineage-specific survival and differentiation programs, therapy-resistant MITF-low/AXL-high melanomas appear to evade these programs and instead depend on alternative survival mechanisms. To uncover such dependencies, we systematically interrogated genome-scale CRISPR-Cas9 knockout screens from the Cancer Dependency Map and identified a selective vulnerability to the epigenetic regulator lysine-specific demethylase 1 (LSD1/ KDM1A ). Intriguingly, domain-focused CRISPR screening spanning whole LSD1 coding locus further revealed that this dependency is mediated through non-catalytic, scaffold-like functions of LSD1 rather than its demethylase activity. Mechanistically, integrated LSD1 ChIP-seq, histone ChIP-seq (H3K4me1/2/3 and H3K27ac) and RNA-seq analyses demonstrated that LSD1 sustains a survival program characterized by chromosome segregation and neuronal dedifferentiation in MITF-low melanoma, orchestrated through distinct super-enhancer activation at key regulators, such as CDC6, related to these pathways. Disruption of LSD1's non-catalytic activity by a LSD1 allosteric inhibitor induced G2/M arrest, transcriptional reprogramming, and growth inhibition selectively in MITF-low melanomas via downregulation of CDC6. Strikingly, genetic and pharmacological ablation of LSD1's non catalytic function significantly prevented or delayed the emergence of resistance to BRAF inhibition and anti-PD-1 therapy in vitro, in vivo, and in patient-derived melanoma organoids. Furthermore, pan-cancer analyses revealed a similar LSD1 dependency in other poorly differentiated malignancies, including pancreatic cancer, that share an undifferentiated transcriptional state. Collectively, these findings define an epigenetically determined, therapeutically targetable state that underlies treatment resistance across multiple cancer types. By targeting the non-catalytic scaffolding function of LSD1, either alone or in combination with targeted and immune therapies, it may be possible to eradicate undifferentiated, drug-tolerant tumor cell populations and overcome therapeutic resistance in melanoma and other aggressive cancers.