PloS one, 2020-07, Vol.15 (7), p.e0235705
2020
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- Autor(en) / Beteiligte
- Titel
- The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer
- Ist Teil von
- PloS one, 2020-07, Vol.15 (7), p.e0235705
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0235705Titel-ID: cdi_plos_journals_2422400092
- Format
- –
- Schlagworte
- Adenosine triphosphatase, Antineoplastic Agents - pharmacology, B7-H1 Antigen - genetics, B7-H1 Antigen - metabolism, Biology and Life Sciences, Biotechnology, Brain cancer, Cancer, Cancer therapies, Carcinoma, Small Cell - genetics, Carcinoma, Small Cell - pathology, Cell Line, Tumor, Cell Proliferation - drug effects, Chromatin remodeling, Chromosomal Proteins, Non-Histone - genetics, Culture Media, Conditioned - chemistry, Culture Media, Conditioned - pharmacology, DNA Helicases - genetics, DNA Helicases - metabolism, DNA-Binding Proteins - antagonists & inhibitors, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Enzyme Inhibitors - pharmacology, Epigenetics, Ewings sarcoma, Female, Gene expression, Gene Expression Regulation - drug effects, Genomics, Histone H3, Histones, Histones - genetics, Histones - metabolism, Humans, Hypercalcemia, Immune checkpoint, Immunity, Immunogenicity, Immunology, Immunotherapy, Inhibitors, Interferon, Interferons - pharmacology, Kinases, Lymphocytes T, Lysine, Medical research, Medicine and Health Sciences, Metastases, Mutation, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Ovarian cancer, Ovarian carcinoma, Ovarian Neoplasms - genetics, Ovarian Neoplasms - immunology, Ovarian Neoplasms - pathology, PD-L1 protein, R&D, Research & development, Research and Analysis Methods, Sucrose, Sugar, T-Lymphocytes - cytology, T-Lymphocytes - drug effects, T-Lymphocytes - immunology, Transcription Factors - antagonists & inhibitors, Transcription Factors - genetics, Transcription Factors - metabolism, Tumors, Womens health