Exploiting NRF2-ARE pathway activation in papillary renal cell carcinoma.

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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.