To explore the molecular mechanism underlying the proliferative advantage of these cells and determine whether critical vulnerabilities exist between targetable PI3K-AKT pathway members and SETD2 loss, we treated SETD2 proficient and SETD2 deficient ccRCC-derived cell lines with a panel of inhibitors targeting PI3Kα (BYL719); PI3Kβ (TGX221, GSK2636, AZD8186); PI3Kδ (Idelalisib); and all PI3K isoforms with a Pan-PI3K inhibitor (BKM120). The gene discussed is AKT1; the disease is nonpapillary renal cell carcinoma.