Abstract 3183: Targeting a myofibroblastic prostate cancer-associated fibroblast subtype through pharmacological inhibition of NADPH oxidase 4

Abstract Recent developments in single cell sequencing have revealed significant heterogeneity in the stromal tumor microenvironment. It is now widely accepted that there are different cancer-associated fibroblast (CAF) subtypes with different functions and effects on tumor progression. Since CAFs are generally considered an emerging therapeutic target, it is crucial to identify those subtypes that are tumor-promoting and to characterize their driver pathways. In this study we describe a population of CAFs in prostate cancer (PCa) that express elevated levels of NADPH oxidase 4 (Nox4) and localize adjacent to tumor foci. We previously showed that Nox4 is essential for TGFβ-mediated differentiation to a myofibroblastic CAF phenotype and that its increased expression is associated with biochemical relapse and reduced survival. Thus, this study aims to investigate whether pharmacological Nox4 inhibition can be used as an adjuvant therapeutic approach in PCa and which molecular pathways are regulated by Nox4 in the tumor microenvironment. Experiments using GKT831, a small molecule Nox1/Nox4 inhibitor with promising effects in clinical trials for fibrotic diseases, so far support its use as a therapeutic target. Most importantly, Nox4 inhibition reduced CAF marker expression in primary prostate CAFs and attenuated the expression of PSA, the key clinical biomarker of PCa progression, in ex vivo cultured human PCa tissue. The translational application of Nox4 inhibition is currently under investigation in vivo using CAF-PCa cell xenografts. To elucidate the molecular mechanisms regulated by Nox4 we performed integrative bioinformatics and functional assays, which revealed that Nox4 regulates CAF adhesion and migration. In addition, we found that Nox4 regulated genes were associated with a YAP signature and the transcription factor TEAD1, a major cofactor of YAP. Ongoing experiments suggest that during adhesion Nox4 signals via oxidation of SHP2, a redox-sensitive phosphatase that has previously been implicated in regulating YAP transcriptional activity. Previous studies have shown that adhesion and mechanotransduction pathways are commonly altered in myofibroblastic CAFs and that they support the formation of a tumor-promoting microenvironment. Our data suggest that Nox4 acts as a central regulator of these key oncogenic pathways and thus represents a promising therapeutic target. Citation Format: Elena Brunner, Lucy Neumann, Elisabeth Damisch, Martin Puhr, Georg Schäfer, Cédric Szyndralewiez, Helmut Klocker, Natalie Sampson. Targeting a myofibroblastic prostate cancer-associated fibroblast subtype through pharmacological inhibition of NADPH oxidase 4 [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 3183.