NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma

similar to 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Although anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8(+)T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

Automated summary

Similar to 30% of ccRCC patients, the presence of metastatic disease at diagnosis results in a low 5-year survival rate of 13%. A study using integrated network analysis has identified NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 promotes tumor growth by enhancing cell cycle progression, glycolysis, and mitochondrial respiration. Immunotherapy is ineffective in NDC80-high ccRCCs, but inhibitors of mitotic kinases PLK1 and AURK show promise as therapeutic options.