Figure 6 from INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors

INX-315 delays the onset of acquired CDK4/6i resistance. A, Representative images from a clonogenic assay in which MCF7 and T47D cells were treated with control vehicle, abemaciclib (500 nmol/L), INX-315 (300 nmol/L for MCF7, 100 nmol/L for T47D), or the combination. Six technical replicates per condition. B, Representative images (right) and quantification (left) after treating MCF7 cells as in A for 7 days followed by staining for beta-galactosidase (β-gal) activity (scale bar = 100 μm). Note that representative images for control and abemaciclib group are identical to those used in Fig. 5A. C, Representative images (right) and quantification of relative nuclear size (left) for cells treated as in B (scale bar = 100 μm). Note that representative images of control and abemaciclib group are identical to those used in Fig. 5B. D, Heat map showing z scores for individual E2F target genes (RNA-sequencing) in MCF7 and T47D cells treated with drugs shown for 7 days at concentrations as in A. Bar plot above shows mean z-score for all genes in each sample. Three technical replicates per condition. E, Tumor growth curves for MMTV-rtTA/tetO-HER2 tumors treated with control vehicle (n = 41 tumors in 5 mice), abemaciclib (n = 40 tumors in 5 mice), INX-315 (n = 39 tumors in 5 mice), or the combination (n = 29 tumors in 5 mice). Experiment was repeated twice. F, GSEA plots derived from RNA-sequencing performed on tumor tissue from experiment (E). Normalized enrichment score (NES) and q value (false discovery rate) were calculated as described in Methods. For B and C, P values calculated using unpaired t test; for E, error bars represent SEM; P values calculated using two-way ANOVA). G, Heat map showing z scores for individual E2F target genes (RNA-sequencing) in MMTV-rtTA/tetO-HER2 tumors from E. Bar plot above shows mean z-score for all genes in each sample. Five samples for vehicle, abemaciclib, and combination; four samples for INX-315.