Fig. 5

A clinically relevant combination therapy delays onset of acquired resistance. a Tumor growth curve and sacrifice time-point (percent survival) in Mel006 PDX tumor bearing mice following treatment with DT (n = 8), DT + TVB-3664 (n = 8), DT + ATO (n = 10) or DT + TVB-3664 + ATO (n = 7). Log-rank (Mantel-Cox) test. b % of Ki67 cancer cells in harvested tumors (n = 4, except for the DT + TVB-3664 + ATO condition where only 3 were available). One-way ANOVA with Tukey’s multiple comparisons. c MDA abundance in harvested tumors (n = 7, except for the DT + TVB-3664 + ATO condition where only 3 were available). One-way ANOVA with Tukey’s multiple comparisons. d Mouse body weight changes in Mel006 PDX tumor bearing mice following treatment with DT (n = 8), DT + TVB-3664 (n = 8), DT + ATO (n = 10) or DT + TVB-3664 + ATO (n = 7). e Summary of observed abnormalities in Mel006 tumor bearing mice. f Sustained MAPK signaling in therapy resistant melanoma cells sustains lipogenesis and generates saturated and monounsaturated fatty acid species which are incorporated into membranes, thereby saturating membranes. This phenomenon renders the cancer cell resistant to ROS mediated membrane lipid peroxidation. Pharmacological inhibition of FASN reverses this effect by blocking lipogenesis and thereby increasing lipid uptake. As exogenous lipids are more enriched in polyunsaturated species, this effect poly-unsaturated membranes, renders the cancer cells ROS sensitive, and can form an actionable clinical strategy. Data represent mean ± SEM. (*p < 0.05, **p < 0.01)