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

  • PLoS One. 2020 Jul 10;15(7):e0235705. doi: 10.1371/journal.pone.0235705.
Raffaella Soldi  1 ,  Tithi Ghosh Halder  1 ,  Alexis Weston  1 ,  Trason Thode  1 ,  Kevin Drenner  1 ,  Rhonda Lewis  1 ,  Mohan R Kaadige  1 ,  Shreyesi Srivastava  2 ,  Sherin Daniel Ampanattu  1 ,  Ryan Rodriguez Del Villar  1 ,  Jessica Lang  3 ,  Hariprasad Vankayalapati  4 ,  Bernard Weissman  5 ,  Jeffrey M Trent  3 ,  William P D Hendricks  3 ,  Sunil Sharma  1
Affiliations
  • 1. Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, Arizona, United States of America.
  • 2. HonorHealth Clinical Research Institute, Scottsdale, Arizona, United States of America.
  • 3. Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, Arizona, United States of America.
  • 4. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
  • 5. Department of Pathology and Laboratory Medicine, Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States of America.
PMID: 32649682 DOI: 10.1371/journal.pone.0235705
Abstract

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

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