Fig. 5: Predicted CDK2/9 inhibition restricts the growth of cervical and bladder cancers in vitro and in vivo.
From: Unbiased discovery of cancer pathways and therapeutics using Pathway Ensemble Tool and Benchmark
a Plots showing the survival rate, measured by CCK-8 assay, of cervical (Hela) and bladder (T24 and UMUC3) cancer cell lines treated with different concentration of vehicle or indicated drugs for 72 h. The selective targets of CDK inhibitors are shown in parenthesis. Mean +/− sem from n > 3 biological replicates. b Plot showing expression of the CDK9 gene versus the unfavorability score for each bladder cancer cell line in the CCLE database22. The color scale represents the IC50 values reported by the GDSC database87 for the CDK9-specific inhibitor CDK9_5038. Cell lines for which IC50 values are not available are highlighted in gray. The Spearman correlation value and corresponding p-value are shown in red. The center line and error bars indicate the trend line and 95% confidence interval. Selected cell lines are labeled. c Heatmap showing differentially expressed genes (DEGs; 3-fold at adjusted p-value < 0.05) between DMSO or CCT068127 (1uM) treated T24 cells for 48 h in n = 3 independent biological replicates. GSEA plots showing enrichment of genes repressed by the CDK4/6 inhibitor Palbociclib (top) or genes repressed by the CDK9 inhibitor VIP152 (bottom) in T24 cells treated 48 h with the CDK2/9 inhibitor CCT068127 (1 uM) or DMSO control. Palbociclib (SRP404373) or VIP152101 inhibited genes are publicly sourced. d GSEA plot showing enrichment of transcriptomes of CCT068127 (1 uM) or DMSO treated T24 cells in favorable (top) or unfavorable (bottom) PET identified prognosis genes in bladder cancer. Shown are the FDR value and normalized enrichment score (NES). e Schematic of xenograft experiment and treatment plan with 30 mg/kg daily i.p. injections of CCT068127 or DMSO carrier. p-values compare DMSO-treated to CCT068127-treated groups at each time-point. f Plot showing daily tumor volumes during course of experiment. g Bar plots showing the mass of tumors at explant on day 23. Error bars show mean ± s.d. p-values in a and f are by two-way ANOVA with multiple comparisons adjustment and in g by two-sided Wilcoxon rank sum test. ns non-significant; *p < 0.01; **p < 0.001; ***p < 0.0001. Panel e Created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license (https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en). Source data are provided as a Source Data file.
