High selectivity of PI3Kβ inhibitors in SETD2-mutated renal clear cell carcinoma.

Purpose Clear cell renal cell carcinoma (ccRCC) is characterized with frequent mutations of SETD2 gene and our purpose was to explore targeted therapy for this entity. Methods By bioinformatic investigation of two major databases, the Genomics of Drug Sensitivity in Cancer (GDSC) database and The Cancer Genome Atlas (TCGA) database, we identified the selective PI3Kβ inhibitors TGX221 and AZD6482 as selective inhibitors for ccRCC with SETD2 mutations, with AZD6482 additionally targeting PIK3CA and CDK6 mutations. Results Further investigation on AZD6482 profile revealed that mutations in RB1, KRAS, NRAS and APC contributed in drug resistance. Changes in both AZD6482-sensitive and -resistant gene sets showed limited impact on prognosis. Western blotting showed AZD6482 did not induce changes in a panel of major downstream effectors of AKT, but substantially increased PMS2 level. AZD6482 also selectively inhibited migration, invasiveness, and colony formation of ccRCC cells with SETD2 mutations. Integrative network analysis revealed complex interactions between these genes except SETD2. Conclusion AZD6482 is a novel inhibitor with high selectivity for ccRCC SETD2 mutations. Increased activity of PI3K/AKT/PMS2 could play a role in SETD2 mutated ccRCC.