SummaryCDDO‐Me has been shown to exert potent anti‐inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO‐Me response in melanoma, we utilized a large‐scale synthetic lethal RNAi screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO‐Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO‐Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO‐Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK‐2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO‐Me efficacy in melanoma growth control.
