Fig. 2.

Rucaparib synergises with BETi in HGSC. (a) Drug screen utilising a 395 compound library in combination with rucaparib on OCI-P5x cells. AUC fold change vs. AUC Z-score of the combination; the size of the dot corresponds to the absolute AUC difference between single agent and combination. Highlighted in red are the top hits: dasatinib and CPI-203. (b) Boxplot of BRD4 mRNA expression across TCGA published datasets sorted by median expression level. (c) Response of OCI-P5x cells to IC30 rucaparib alone and in combination with the BETi CPI-0610, JQ1, I-BET726, OTX015, CPI-203. (d) Dose-response plots of olaparib and niraparib in combination with the BETi CPI-203 or CPI-0610 demonstrating synergistic drug combination effects in OCI-P5x cells. (e) Mutation enrichment of BRD4 overexpression (Z-score > 2) or copy number amplification in TCGA HGSC, demonstrating that BRCA1 and BRCA2 mutations are mutually exclusive with BRD4 overexpression or amplification. (f) Tumour weights from in vivo study examining the rucaparib and CPI-0610 combination using OCI-P5x xenografts. Box-and-whisker plots are presented according to the Tukey method: **p < 0.01, ****p < 0.0001, ns=not significant (one- way ANOVA followed by Tukey's test).