Fig. 4.

Navitoclax and rucaparib synergise in cancers with DNA repair mutations. (a) Drug screen utilising a 395-compound library in combination with rucaparib on OCI-C5x 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 is the top hit, navitoclax. (b) Dose-response plots of rucaparib in combination with navitoclax demonstrating synergistic drug combination effects in OCI-C5x, OCI-C4p, OVCAR8, and KURAMOCHI cells, but little synergy in OCI-P5x and FCI-P2P cells. (c) Western blot analysis of PARP and cleaved PARP levels in OCI-C5x and OCI-C4p cells in response to rucaparib (10 μM) and navitoclax (1 μM) for 48 h. Blots shown are representative of at least three independent experiments. (d) OCI-C5x cells were treated with siRNA specific to BCL2L1 and BCL2L2 for 48 h. Cells were subsequently treated with rucaparib for a further 6 days before cell viability was measured. Representative of 3 independent experiments, data is presented as mean ± SEM. (e) mRNA expression levels of 770 genes in OCI-C5x and OCI-P5x cells. Highlighted in red are genes involved in apoptosis. OCI-C5x has higher BCL2L1 mRNA expression compared to OCI-P5x. (f) Correlation of BCL2L1 expression with BRCA1/2, MSH2/6, and BARD1 expression in The Cancer Genome Atlas (TCGA): high grade serous ovarian carcinoma (HGSC), breast invasive carcinoma (BRCA), prostate adenocarcinoma (PRAD), and colon adenocarcinoma (COAD).