8P Biomarkers to predict chemotherapy response in low-grade serous ovarian carcinoma

Low-grade serous ovarian carcinoma (LGSC) is a rare subtype with distinctive genomic characteristics and low response to platinum chemotherapy. Outcomes for advanced LGSC are poor, therefore treatment options, including non-platinum chemotherapy need to be explored. Importantly, predictive biomarkers are needed to avoid exposure to toxic ineffective treatments. We aimed to identify molecular features predictive of response to docetaxel, paclitaxel and gemcitabine in well-defined LGSC cell line models. Cell viability was assessed following docetaxel, paclitaxel and gemcitabine exposure in eight LGSC lines (CellTiter 96™ MTS Assay, Promega). RNA was sequenced (RNAseq, Illumina HiSeq2000) and analysed using EdgeR & clusterProfiler. The LGSC cell lines had MAPK pathway variants that are reflective of clinical samples (Table). HOC7 was relatively sensitive to all three agents. MPSC1 was sensitive to docetaxel and gemcitabine, and HO433 was only sensitive to gemcitabine. WMINV10, WMOV24 and WMINV13 were relatively resistant to all agents. There was no association between RAS/RAF mutation and drug response.Table: 8PIC50 (nM) of LGSC cell lines, ordered by docetaxel IC50Cell LineRAS/RAF MutationDocetaxel IC50Paclitaxel IC50Gemcitabine IC50MPSC1BRAFV600L, NRASQ61R1.86.110HCC5075KRASG12V21.518HOC7KRASG12A2.11.75AOCS2WT6.611.429WMINV10KRASG12V38.2NR1669WMOV24KRASG12D95NR1038HO433WT103113.85.1WMINV13NRASQ61RNRNR3451WT = wild type; NR= not reached. Open table in a new tab WT = wild type; NR= not reached. Transcriptome analysis showed epithelial to mesenchymal transition genes to be strongly associated with resistance to docetaxel (Gene Set Enrichment Analysis, GSEA q=2.1x10-10) and paclitaxel (GSEA q=1.1x10-10) whereas pathways involving DNA replication were upregulated in cell lines sensitive to docetaxel (p-adj=0.0004). Neuronal system pathways were upregulated in cell lines resistant to gemcitabine (p-adj=9.4x10-11) and docetaxel (p-adj=2.8x10-12). Our pre-clinical data suggests that non-platinum chemotherapy may be a viable option in selected LGSC patients. Gene expression profiles associated with response to specific agents were identified. However, these findings need further validation in patient samples.