The Nrf2-ARE pathway: a potential novel therapeutic target in papillary Renal Cell Carcinoma patients

Papillary renal cell carcinoma (pRCC) is an aggressive tumour subtype accounting for 15 to 20% of RCCs. Activation of the Nrf2-ARE pathway, which sense and responds to increases in oxidative stress, has been shown to be a potential characteristic mechanism in pRCC. In cancer cells, stabilisation of Nrf2 results in enhanced expression of tumour-associated factors, among them NQO1, a reductase that prevents the production of ROS. Comprehensive molecular characterization of 60 FFPE pRCCs by copy number analysis and Whole Exome Sequencing allowed us to identify pRCC groups based on their genetic background. Protein expression of NQO1 was analysed by immunohistochemistry and activity assay. Newly established patient-derived cell models that resemble pRCC tumours were applied for drug profiling with Nrf2-ARE pathway inhibitors. Immunohistochemical tissue microarray analysis of 638 RCC tumours correlated Nrf2-ARE pathway over-activation with worse patient outcome and higher tumour grade and stage in pRCC. Secondly, we identified mutations in 4 key genes of this pathway (NFE2L2, Keap1, CUL3 and Bach1) in 12% of all samples. The investigation of 9 matched pRCC and patient-derived tumour cell cultures demonstrated increased NQO1 mRNA and protein expression and activity in 56% of tumours. Finally, drug screening with Nrf2-ARE pathway inhibitors using 6 pRCC PDCs identified Brusatol and Convallatoxin, two Nrf2 inhibitors, as potential novel treatments in pRCC. RCC is an aggressive disease with heterogeneous molecular background that bring to a lack of targeted treatment options. We showed that inhibition of Nrf2 represents a promising therapeutic target for this tumour subtype.