The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

• DOI: 10.1371/journal.pone.0235705
• Publication Date: 2020-07-10T17:34:27Z
• Authors: Raffaella Soldi; Tithi Ghosh Halder; Alexis Weston; Trason Thode; Kevin Drenner; Rhonda Lewis; Mohan R. Kaadige; Shreyesi Srivastava; Sherin Daniel Amp...; Ryan Rodriguez de...; Jessica Lang; Hariprasad Vankay...; Bernard Weissman; Jeffrey M. Trent; William P. D. Hen...; Sunil Sharma
• Keywords: SMARCA4; ARID1A; Clear cell carcinoma

Mutations of the SWI/SNF chromatin remodeling complex occur in 20% all human cancers, including ovarian cancer. Approximately half clear cell carcinomas (OCCC) carry mutations subunit ARID1A, while small carcinoma ovary hypercalcemic type (SCCOHT) presents with inactivating ATPase SMARCA4 alongside epigenetic silencing SMARCA2. Loss these ATPases disrupts activity and may also interfere function other histone-modifying enzymes that associate or are dependent on activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A), which regulates landscape gene expression by demethylating proteins as H3. Cross-cancer analysis TCGA database shows LSD1 highly expressed SWI/SNF-mutated tumors. SCCOHT OCCC lines have shown sensitivity to reversible inhibitor SP-2577 (Seclidemstat), suggesting SWI/SNF-deficient cancers Moreover, it has been inhibition stimulates interferon (IFN)-dependent anti-tumor immunity through induction endogenous retroviral elements thereby overcome resistance checkpoint blockade. In this study, we investigated ability promote T-cell infiltration lines. We found stimulated IFN-dependent promoted PD-L1 both OCCC. Together, findings suggest combination therapy inhibitors induce augment immunogenic responses warrants further investigation.