NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis

  • EMBO Rep. 2025 Jun;26(12):3106-3137. doi: 10.1038/s44319-025-00463-z.
Ryan J Conrad  #  1 ,  James A Mondo  #  2 ,  Mike Lingjue Wang  3 ,  Peter S Liu  4 ,  Zijuan Lai  3 ,  Feroza K Choudhury  3 ,  Qingling Li  4 ,  Weng Ruh Wong  4 ,  James Lee  1 ,  Frances Shanahan  1 ,  Eva Lin  1 ,  Scott Martin  1 ,  Joachim Rudolph  5 ,  John G Moffat  6 ,  Dewakar Sangaraju  3 ,  Wendy Sandoval  4 ,  Timothy Sterne-Weiler  7  8 ,  Scott A Foster  9
Affiliations
  • 1. Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA, 94080, USA.
  • 2. Roche Informatics, F. Hoffmann-La Roche Ltd., Mississauga, ON, Canada.
  • 3. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, 94080, USA.
  • 4. Department of Microchemistry, Proteomics & Lipidomics, Genentech, Inc., South San Francisco, CA, 94080, USA.
  • 5. Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA, 94080, USA.
  • 6. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA, 94080, USA.
  • 7. Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA, 94080, USA. [email protected].
  • 8. Department of Oncology Bioinformatics, Genentech, Inc., South San Francisco, CA, 94080, USA. [email protected].
  • 9. Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA, 94080, USA. [email protected].
  • # Contributed equally.
PMID: 40369363 DOI: 10.1038/s44319-025-00463-z
Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers (NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in Cancer cell lines, and observed that a significant portion of these genes is devoid of promoter-proximal NRF2 occupancy. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent Cancer cell growth does not require this enhanced glutathione production.

Keywords
CBP/p300; Glutathione; NRF2; Non-small Cell Lung Cancer; ROS.
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