Chemotherapy-induced dynamic gene expression changes in vivo are prognostic in ovarian cancer

This work was supported by Medical Research Scotland (FRG353 to VAS), the FP7-Directorate-General for Research and Innovation of the European Commission (EU HEALTH-F4-2012-305033 to Coordinating Action Systems Medicine to DJH); the Chief Scientist Office of Scotland (to DJH) and the Scottish Funding Council (to DJH and SPL).Background: The response of ovarian cancer patients to carboplatin and paclitaxel is variable, necessitating identification of biomarkers that can reliably predict drug sensitivity and resistance. In this study, we sought to identify dynamically controlled genes and pathways associated with drug response and its time dependence. Methods: Gene expression was assessed for 14 days post-treatment with carboplatin or carboplatin–paclitaxel in xenografts from two ovarian cancer models: platinum-sensitive serous adenocarcinoma-derived OV1002 and a mixed clear cell/endometrioid carcinoma-derived HOX424 with reduced sensitivity to platinum. Results: Tumour volume reduction was observed in both xenografts, but more dominantly in OV1002. Upregulated genes in OV1002 were involved in DNA repair, cell cycle and apoptosis, whereas downregulated genes were involved in oxygen-consuming metabolic processes and apoptosis control. Carboplatin–paclitaxel triggered a more comprehensive response than carboplatin only in both xenografts. In HOX424, apoptosis and cell cycle were upregulated, whereas Wnt signalling was inhibited. Genes downregulated after day 7 from both xenografts were predictive of overall survival. Overrepresented pathways were also predictive of outcome. Conclusions: Late expressed genes are prognostic in ovarian tumours in a dynamic manner. This longitudinal gene expression study further elucidates chemotherapy response in two models, stressing the importance of delayed biomarker detection and guiding optimal timing of biopsies.Peer reviewe