Fig. 6: Synthetic lethality of IAP inhibitors towards SOX10-deficient population.

a Synthetic lethality of IAP1/2-XIAP inhibitors toward the SOX10-deficient population expressed as inhibition of cell viability. b The same number of cells were seeded for each cell line. Cells were treated with increasing concentrations of birinapant. Treatment was renewed every 48 h. Shown is the mean ± SD from three independent experiments. p-values were calculated using two-sided model-based t-test tests and adjusted for multiple testing using the Hochberg method and represent statistical analysis comparing birinapant-induced growth inhibition in MeWo parental vs MeWo #2.1 and MeWo #4.11. p-values are shown. c Cell lysates were western blotted, as indicated. The experiment was repeated independently three times with similar results. d scRNA-seq cell line data for SOX10 and cIAP2/BIRC3. p < 0.001 for zero-inflation model and p = 0.002 for mean model. e Cells were treated with PLX4720 (1 µM) + PD0325901 (35 nM) for 24 h, lysed and western blotted. The experiment was repeated independently three times with similar results. f The same number of cells were seeded for each cell line. Cells were treated with increasing concentrations of birinapant. Treatment was renewed every 48 h. Shown is the mean ± SD from three independent experiments. p-values were calculated and adjusted as in b. and represent statistical analysis comparing birinapant-induced growth inhibition in A375 parental vs CRT35 or CRT34 cells. p-values are shown. g A375 xenograft tumor growth, day 0 corresponding to the first day of treatment. Mice were treated 200 PPM PLX4720 plus 7 PPM PLX2695 and/or injected with 100 μL (for female mice) or 150 μL (for male mice) birinapant solution (3 mg/ml). AIN-76A diet was used as vehicle. Number of mice per cohort as indicated. Statistical significance was calculated as the time to tumor regrowth (tumor volume > 100 mm³) and corresponding median survival times were estimated using the Kaplan–Meier method. The two-sided log-rank test was used to compare the time to regrowth between treatment groups. p-value is shown. h Mouse survival curve for the in vivo experiment shown in g. p-values were calculated using the two-sided log-rank tests and were adjusted for multiple testing to control for the False Discovery Rate (FDR) using the method of Benjamini and Hochberg. p-values are shown.