Fig. 5.

Fulvestrant potentiates MDM2 inhibition in vivo in a PDX model of fulvestrant-resistant ER+ breast cancer. a Growth of the endocrine-resistant Gar15-13 PDX model of ER+ breast cancer treated with vehicle (2% DMSO daily, grey, n = 7), NVP-CGM097 (100 mg/kg daily, red, n = 8), fulvestrant (5 mg/body weekly, blue, n = 8) or the combination of NVP-CGM097 and fulvestrant (purple, n = 9). b Continued growth of tumours following withdrawal of treatment after 6 weeks. c Survival analysis of outcomes after treatment with combination therapy compared to each drug alone (an event was defined as a tumour exceeding 999 mm³). Curves were compared using Mantel-Cox log-rank test and significance is indicated for comparisons of each arm with vehicle. d Representative images and quantification of IHC staining for Ki-67 of three independent replicates per treatment arm from tumours treated for 10 days. Statistical significance from Tukey’s multiple comparison test is indicated. Bar = 50 μm. e GSEA analysis compared to vehicle performed across gene expression sets of in vitro and in vivo models following treatment with NVP-CGM097 (red), fulvestrant and combination therapy show consistent regulation of hallmark signatures from MSigDB: E2F targets, G₂/M checkpoints, MYC targets and p53 pathway. This analysis is reinforced by the normalised enrichment score (NES) that shows the difference in gene set size following each treatment conditions