Fig. 5: PDX Models Exhibit Distinct Transcriptomic Signatures Based on Time to CDK4/6i Progression.

A Timeline and volume growth curves of tumor establishment in PDX models derived from patients who progressed after ≥6 months of CDK4/6 inhibitor therapy (PR-1 and PR-2). Tumors were passaged through transplantation to generate Passage 2 (P2),P3 and P4 tumors. B Doubling time of PR-1 and PR-2 tumors from P2 (n = 2), P3 (n = 3), and P4 (n = 3). C Timeline and volume growth curves of tumor establishment in the PDX models from patients who progressed within 3 months of CDK4/6i therapy (PR-3 and PR-4). D Doubling time of PR-3 and PR-4 tumors from P2 (n = 4), P3 (n = 3), and P4 (n = 4). E Representative images of hematoxylin and eosin (H and E) staining; immunohistochemical staining of hormone receptor status: ER, PgR, and HER2; and Ki67. F Total number of mutations in each PDX model identified by whole exome sequencing. G Venn diagram of the type of mutations shown in panel (F). H Hierarchical clustering heat map of differentially expressed genes (DEGs) between PDX models derived from patients who progressed within 3 months of CDK4/6i therapy (yellow bar) and those who progressed after ≥6 months (green bar). RNA sequencing carried out on six tumors from each PR PDX model collected at P3 and P4. Red denotes genes with increased expression levels and blue indicates genes with decreased expression levels. I Volcano plot revealing 3386 upregulated (red) and 2829 downregulated (blue) significant DEGs in PDX models from patients who progressed after ≥6 months compared with those who progressed within 3 months. J Gene set enrichment analysis comparing PDX models from patients who progressed after ≥6 months vs. those who progressed within 3 months. Starred pathways overlap with those found in our previously published PR cell line models. K Average Spearman Correlation of PR PDX Models to the acquired resistance cell line signature (corresponding to ≥6-month progression). L Ward clustering heat map of the 50-gene signature for PAM50 subtyping of each PDX model or cell line. M Western blot analysis with the indicated antibodies from each PR PDX model collected at P3 and P4.