Exploiting NRF2-ARE pathway activation in papillary renal cell carcinoma

Int J Cancer. 2025 Apr 1;156(7):1457-1469. doi: 10.1002/ijc.35311. Epub 2024 Dec 20.

Abstract

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cancer subtype but has no indicated targeted treatments. MET inhibition may be a treatment for MET-driven pRCC, but there is a large group of non-MET-driven pRCC without targeted therapy. Activation of NRF2-ARE pathway has been suggested to be involved in pRCC. To study the relevance of the NRF2-ARE pathway, we characterized 60 pRCCs by copy number analysis and Whole Exome Sequencing. Because stabilisation of NRF2 results in enhanced expression of NQO1, a reductase that prevents production of reactive oxygen species, protein expression of NQO1 was analysed by immunohistochemistry (IHC) from tissue microarrays (TMAs) and by enzymatic activity assay. Finally, patient-derived pRCC cells (PDCs) were applied for drug profiling with 18 NRF2-ARE pathway inhibitors. We identified MET mutations in 5%, and mutations in four genes of NRF2-ARE pathway (NFE2L2, KEAP1, CUL3 and BACH1) in 10% of 60 pRCC samples. IHC analysis of TMAs of 638 renal cancers showed the correlation of the expression of NQO1 with poor survival outcome (p < .001) and high tumour grade (p < .001) and stage (p < .001) in pRCC. NQO1 mRNA, protein levels and enzymatic activity were increased in 56% of matched pRCC tissue samples and patient-derived cells (PDCs, n = 9). Drug screening revealed that Brusatol and Convallatoxin are potential novel drugs for pRCC. Inhibition of NRF2 represents a novel therapeutic approach for MET-independent pRCC patients.

Keywords: NQO1; NRF2‐ARE pathway; drug sensitivity profiles; papillary renal cell carcinoma; patient‐derived cells; translational medicine.

MeSH terms

  • Aged
  • Antioxidant Response Elements / genetics
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Carcinoma, Renal Cell* / pathology
  • Exome Sequencing
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Male
  • Middle Aged
  • Mutation
  • NAD(P)H Dehydrogenase (Quinone)* / genetics
  • NAD(P)H Dehydrogenase (Quinone)* / metabolism
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • Proto-Oncogene Proteins c-met
  • Signal Transduction

Substances

  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • KEAP1 protein, human
  • MET protein, human
  • Proto-Oncogene Proteins c-met