Identification of unique sensitizing targets for anti‐inflammatory CDDO ‐ M e in metastatic melanoma by a large‐scale synthetic lethal RNA i screening

Summary CDDO ‐ M e 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 ‐ M e response in melanoma, we utilized a large‐scale synthetic lethal RNA i screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO ‐ M e. Based on screening results, five unique genes ( GNPAT , SUMO 1 , SPINT 2 , FLI 1 , and SSX 1 ) significantly potentiated the growth inhibitory effects of CDDO ‐ M e and induced apoptosis in A 375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO ‐ M e activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated E rk1/2, A kt, GSK ‐2, and PRAS 40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT , SUMO 1, SPINT 2, FLI 1, and SSX 1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO ‐ M e efficacy in melanoma growth control.