Fig. 6: 108600 suppresses growth of TNBC cell line and PDX tumor grafts.
A 108600 inhibits phosphorylation of CK2α and DYRK1A substrates in vivo. NSG mice bearing CTG1883 PDX tumor grafts were treated with 108600 (100 mg/kg) or DMSO for 5 days (n = 5). Box plots show levels of phospho-AKT1Ser129 and phospho-CYCLIN D1Thr 286 normalized to those of their respective total proteins and GAPDH. Variances were tested using F-tests (two-sided). P values were calculated using a t-test (two-sided). Samples derive from the same experiment and the blots processed in parallel. B Nude mice bearing MDA-MB-231 xenografts were treated with vehicle or 108600 (50 mg/kg or 100 mg/kg) for 21 days. Tumor volumes were measured on the indicated days. (n = 7 for vehicle- and 108600 (100 mg/kg)-treated animals; n = 6 for 108600 (50 mg/kg)-treated animals). Statistical differences were assessed by two-way ANOVA (two-sided). Data represent mean ± SEM. C 108600 suppresses growth of paclitaxel-sensitive PDX tumors. TM00098 tumor-bearing NSG mice were randomly assigned to groups and treated with vehicle (n = 4) or 108600 (100 mg/kg q2D) (n = 5). Error bars represent mean ± SEM. Statistical differences were assessed by two-way ANOVA (two-sided). D Chemotherapy-resistant PDX growth suppression by 108600. PDX models were treated with DMSO (n = 5 for CTG1883; n = 7 for CTG2397), paclitaxel (10 mg/kg, n = 6 for CTG1883; n = 5 for CTG2397), 108600 (100 mg/kg, n = 6 for CTG1883; n = 7 for CTG2397) or a combination of paclitaxel and 108600 (n = 6 for CTG1883; n = 6 for CTG2397). Paclitaxel and 108600 were administered q4d and q2d, respectively. Statistical differences were assessed by two-way ANOVA (two-sided). Weights of tumors harvested at study endpoints are shown. Data represent mean ± SD. Statistical differences were assessed using a t-test with false discovery rate correction calculated by the Benjamini–Hochberg method. Experiments were performed twice with each model. E 108600 decreased the ALDHhigh fraction in CTG2397 organoids. ALDH activity was measured in organoids treated with 108600 for 48 h. DEAB-treated organoids served as negative controls. Mean values ± SD from three independent experiments are shown. Statistical differences between the ALDHhigh fractions were tested using one-way ANOVA (two-sided) and Dunnett’s test (two-sided). p values of less than 0.05 were considered statistically significant. Source data are provided as a source data file.
