Abstract 1165: Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer

Abstract

Abstract The Nuclear receptor Glucocorticoid receptor (GR) acts as a ubiquitous hormone-dependent transcription factor, which regulates many cellular functions. Here, we discovered that some ETS (E-twenty-six) family transcription factors form physical complexes with GR. Two members of the family, FLI1 and ERG exhibited stronger binding with the ligand-activated GR. GR-FLI1 interaction enhance the transcriptional activity of DNA-bound GR. Antagonizing GR or lowering cortisol levels in Ewing sarcoma (ES) animal models, a pediatric bone malignancy driven by EWS-FLI1 fusion, robustly retarded tumor growth, as well as inhibited bone to lung metastasis. These findings prompted us to identify prognostic, GR-regulated gene signature in ES. Because the genomic binding sites of GR in ES are still unknown, using chromatin immunoprecipitation followed by high-throughput DNA sequencing in A673 cells we found previously known and new target genes of GR. By utilizing the protein-fragment complementation assay (PCA), we discovered that GR physically interacts with additional ETS factors. Disruption of this complex is enabled by clinically approved GR antagonist RU486 or newly developed selective GR modulators (i.e., SGRMs without AR or PR cross-reactivity). ETS proteins has been strongly associated with tumor progression and metastasis in several cancers. Taken together, we hypothesised that these mechanisms are also relevant for other ETS rearranged cancers. Results of co-immunoprecipitation analysis confirm the interaction of GR and ERG/ETV4 in ETS-positive prostate cancer cells. In addition, migration and proliferation were reduced when we knocked-down or antagonized GR. It is important noting that the pharmacology of GR is very well developed and some GR-targeting drugs are among the most prescribed medicines. These discoveries will open the way to clinical tests and eventual application of anti- hormone therapy in the discipline of pediatric sarcomas and ETS-rearranged cancers. Citation Format: Arunachalam Sekar, Nishanth Belugali Nataraj, Yosef Yarden. Therapeutic targeting of glucocorticoid receptor in ETS rearranged cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1165.