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

Abstract

Chromatin remodeling SWItch/Sucrose-NonFermentable (SWI/SNF) complexes, initially identified in yeast 20 years ago, are evolutionarily conserved multi-subunit protein complexes that use the energy from hydrolysis of adenosine triphosphate (ATP) to remodel nucleosome structure and modulate transcription. Mutations in proteins of SWI/SNF complexes occur in 20% of human cancers including ovarian cancer (OC). Approximately 50% of ovarian clear cell carcinoma (OCCC) carries mutations in the SWI/SNF subunit ARID1A while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is driven primarily by genetic inactivation of the SWI/SNF ATPase SMARCA4 (BRG1) alongside epigenetic silencing of the homolog ATPase SMARCA2 (BRM). Dual loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may alsointerfere 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, including histone H3. LSD1 associates with epigenetic complexes such as the nucleosome remodeling deacetylase complex (NuRD) and SWI/SNF to inhibit the transcription of genes involved in tumor suppression and cell differentiation. TGCA analysis of human cancers shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. Further, SCCOHT and OCCC cell lines show low nM IC 50 s for the reversible LSD1 inhibitor SP-2577 (Seclidemstat, currently in clinical phase I trials), supporting that these SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Recently, it has been also shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of Endogenous Retroviruses Elements (ERVs) and may thereby overcome resistance to checkpoint blockade. Additionally, SCCOHTs have been shown to exhibit an immune-active tumor microenvironment with PD-L1 expression in both tumor and stromal cells that strongly correlated with T cell infiltration. Thus, in this study we investigated the ability of SP-2577 to promote anti-tumor immunity and T cell infiltration in SWI/SNF-mutant SCCOHT and OCCC models. Our data shows that the reversible LSD1 inhibitor SP-2577 stimulates IFN-dependent anti-tumor immunity in SCCOHT cells in vitro in a 3D immuneorganoid platform. Additionally, SP-2577 promoted the expression of PD-L1 in both SCCOHT and OCCC models. Together our findings suggest that SP-2577 and checkpoint inhibitors as a therapeutic combination may induce or augment immunogenic responses in these tumors.

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)

“…A large number of preclinical studies have revealed the critical role of epigenetic factors in antitumor immune responses and reversal of immunosuppression, particularly in PD-L1/PD-1 blockade (72,91,172,184). The rational application of a combination of multiple epigenetic targeted drugs, including DNMT inhibitors and histone-modifying enzyme inhibitors, with anti-PD-L1 immunotherapy, represents an opportunity to improve antitumor efficacy, enhance response rates to PD-1/PD-L1 blocking antibodies and reverse drug resistance.…”

“…Lysine demethylase 4B (KDM4B) is a demethylase that acts on lysine, and its silencing can reduce PD-L1 expression by promoting H3K27me3 expression and reducing homeobox C4 (HOXC4) expression in colorectal cancer cells (90). In addition, lysine-specific histone demethylase 1 (LSD1) regulates the chromatin landscape and gene expression by demethylating proteins, such as histone H3 (91). HCI-2509, a noncompetitive highly potent reversible LSD1 inhibitor, upregulates PD-L1 expression in breast cancer cells in a dose-dependent manner (92).…”

“…HCI-2509, a noncompetitive highly potent reversible LSD1 inhibitor, upregulates PD-L1 expression in breast cancer cells in a dose-dependent manner (92). SP-2577, which is currently undergoing a phase I clinical trial, is also a potent and reversible LSD1 inhibitor that can promote PD-L1 expression in small cell carcinoma of the ovarian hypercalcemic type cells by inhibiting LSD1 (91). Based on these developments, LSD1 inhibition may be a promising epigenetic adjunctive therapy to ICIs.…”

Clinical advances in targeting epigenetics for cancer therapy

“…Recently, LSD1 has proven to be highly expressed in SWI/SNF‐mutant cancers. Inhibition of LSD1 by SP‐2577 reduces the proliferation of SWI/SNF‐deficient ovarian cancer cell lines, suggesting SP‐2577 as a treatment for this cancer type [85].…”

The role of interferons in ovarian cancer progression: Hinderer or promoter?

“…SP-2577 is an LSD1 inhibitor. SP-2577 promoted ERV expression in ovarian cancer cells and activated the dsRNA-induced IFN pathway, which facilitated cytokine expression and infiltration of immune cells in ovarian hypercalcemic organoids (103). CX-5461, an RNA polymerase I inhibitor, led to the accumulation of cytoplasmic dsDNA activating the cGAS-STING-TBK1-IRF3 innate immune pathway, which induced IFN-I and promoted the secretion of IL-6 and CXCL10, contributing to T cell infiltration (104).…”