Angori Silvia, Lakshminarayanan Harini, Banaei-Esfahani Amir, Mühlbauer Katharina, Bolck Hella Anna, Kallioniemi Olli, Pietiäinen Vilja, Schraml Peter, Moch Holger
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
Institute for Molecular Medicine Finland-FIMM, Helsinki Institute of Life Science-HiLIFE, University of Helsinki, Helsinki, Finland.
Int J Cancer. 2025 Apr 1;156(7):1457-1469. doi: 10.1002/ijc.35311. Epub 2024 Dec 20.
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.
乳头状肾细胞癌（pRCC）是第二常见的肾癌亚型，但尚无明确的靶向治疗方法。抑制MET可能是治疗MET驱动的pRCC的一种方法，但有一大类非MET驱动的pRCC没有靶向治疗。NRF2-ARE途径的激活被认为与pRCC有关。为了研究NRF2-ARE途径的相关性，我们通过拷贝数分析和全外显子测序对60例pRCC进行了特征分析。由于NRF2的稳定会导致NQO1表达增强，NQO1是一种可防止活性氧产生的还原酶，因此通过组织微阵列（TMA）的免疫组织化学（IHC）和酶活性测定分析了NQO1的蛋白表达。最后，将患者来源的pRCC细胞（PDC）用于18种NRF2-ARE途径抑制剂的药物筛选。我们在60例pRCC样本中的5%中发现了MET突变，在10%中发现了NRF2-ARE途径的四个基因（NFE2L2、KEAP1、CUL3和BACH1）的突变。对638例肾癌TMA的IHC分析显示，pRCC中NQO1的表达与不良生存结果（p < 0.001）、高肿瘤分级（p < 0.001）和分期（p < 0.001）相关。在56%的匹配pRCC组织样本和患者来源细胞（PDC，n = 9）中，NQO1 mRNA、蛋白水平和酶活性增加。药物筛选显示，布鲁斯他汀和铃兰毒苷是pRCC潜在的新型药物。抑制NRF2代表了一种针对非MET依赖性pRCC患者的新型治疗方法。
