Abstract PR16: A druggable transcriptional vulnerability in NRF2-dependent lung cancer

The b-ZIP transcription factor NRF2 is a master regulator of the cellular antioxidant response and frequently activated in Non-Small Cell Lung Cancers (NSCLCs). While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires metabolic and signaling networks in cancer cells that may create special vulnerabilities for therapeutic intervention. Here, we use chemical proteomics to map ligandable proteins in NRF2-activated NSCLC cells, leading to the discovery of metabolic and transcriptional pathways that are strictly regulated by NRF2. Principal among these was the orphan nuclear receptor NR0B1, which we show nucleates a multimeric protein complex required for the transcriptional output and anchorage-independent growth of NRF2-driven cancers. We further identify small-molecules that target a conserved cysteine within NR0B19s protein interaction domain and show that these chemical probes disrupt NR0B1 complexes and NRF2-dependent cancer cell growth. Our findings thus designate NR0B1 as a druggable, transcriptional co-dependency target for NRF2-activated lung cancers. Citation Format: Liron Bar-Peled, Esther Kemper, Benjamin Cravatt. A druggable transcriptional vulnerability in NRF2-dependent lung cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR16.