Fig. 3
CDC7 inhibition suppresses NE transformation. a In vivo treatment of cell line xenografts for TP53/RB1-inactivated (DKO) LnCap/AR and 22PC cells with vehicle (N = 8 for LnCap/AR and N = 4 for 22PC) enzalutamide (N = 10, N = 6), simurosertib (N = 9, N = 4) or their combination (N = 10, N = 7). b Barplot showing the average ± standard deviation of the intratumoral percentages of adenocarcinoma and NE histology in tumors collected at endpoint for each treatment arm, including vehicle (N = 5), enzalutamide (N = 7), simurosertib (N = 6) and their combination (N = 4). Barplot showing the average ± standard deviation of H-score quantification (c) and representative images (d) for immunohistochemical assessment of the expression of androgen receptor (AR), synaptophysin (SYP) and chromogranin A (CHGA) staining in LnCap/AR tumors collected at endpoint for each experimental arm. e Trajectory analyses on single-cell transcriptomic data for the control and enzalutamide-treated DKO LnCap/AR tumors, illustrating changes in expression of gene of interest and in enrichment for gene signatures of interest. The lower panel consists of a heatmap of gene trends of select genes of relevance in NE transformation ordered by the putative transition from adenocarcinoma to NEPC in control and enzalutamide-treated cells from the in vivo treatment experiment in Fig. 3a. The top panel shows a spline fit of the average Z-score for GSEA pathways of interest. f H&E and IHC staining for markers of interest for the EGFR-mutant combined NSCLC/SCLC PDX tumor MSK_Lx151. g In vivo treatment of the MSK_Lx151 PDX with vehicle (N = 5), Osimertinib (N = 6), simurosertib (N = 5) or their combination (N = 7). For a–c and j, p-values were calculated using the Student’s t test (unpaired, heterogeneous variances, two-tailed). p-value legend: *<0.05, **<0.01, ***<0.001, ****<0.0001, ns not significant
