Abstract 5728: A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC

Abstract

Abstract FOXA1 is a pioneer factor that is essential to steroid receptor function in hormone-dependent adenocarcinomas, including breast and prostate cancer. FOXA1 expression is also observed in other tumors of epithelial lineage such as non-small cell lung cancer (NSCLC), but whether and how it is required for tumor growth in these contexts is not known. Analyzing data from genome-scaled pooled loss-of-function screens, we identified and validated a subset of NSCLC cell lines with reduced cellular fitness following FOXA1 knockout. We performed a rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME) screen to nominate candidate factors that may cooperate with FOXA1 to mediate oncogenic transcription programs. This screen revealed a chromatin-localized interaction between FOXA1 and the glucocorticoid receptor (GR). Depletion of GR expression using shRNA or CRISPR/Cas9 suppressed the proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC models, suggesting GR specifically contributes to tumor growth in the FOXA1-dependent context. To assess the potential therapeutic utility of targeting the FOXA1-GR signaling axis, we employed two structurally distinct ligand antagonists of GR from ORIC Pharmaceuticals: ORIC-101, a steroidal antagonist, and OP-4954, a non-steroidal antagonist. Both antagonists inhibited dexamethasone stimulated GR-transactivation of a glucocorticoid response element (GRE)-luciferase reporter with equal potency. However, proliferation and colony formation of the FOXA1/GR-dependent NSCLC cells were only inhibited upon treatment with ORIC-101, and not OP-4954. Gene expression analysis uncovered a discrete set of GR target genes, including SFTPB, TRAF4 and SGK1, whose expression was reduced by ORIC-101 but unaffected or even induced by OP-4954. The specific inhibition of GR target gene expression and attendant induction of apoptosis by ORIC-101 suggest a hierarchy of GR targets relevant to the FOXA1/GR-growth program in NSCLC. Finally, we evaluated the in vivo therapeutic potential of ORIC-101 using NSCLC xenografts and found that single-agent ORIC-101 exhibited potent antitumor effects in these models. Taken together, these data establish a model of FOXA1-GR-dependent tumor growth amongst a subset of NSCLCs and demonstrate that effective blockade of this complex is a rational therapeutic avenue to be explored in the clinic. Citation Format: Madeline Dorso. A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in NSCLC [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 5728.