Chemo-mediated transcriptional reprogramming in ovarian cancer

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Abstract High-grade serous carcinoma (HGSC) is the most aggressive OC subtype that accounts for 80% of OC-related deaths. Rapid emergence of platinum (Pt)-resistance is the main reason for this mortality. Despite initial response to surgery plus chemotherapy, tumors relapse and rapidly become chemoresistant in 80% of patients. Although few genetic mutations have been associated with chemoresistance, in a large fraction of tumors, drivers of the chemoresistance's rapid emergence are unknown. Here we propose that non-genetic mechanisms play an important part in regulating cellular transition to a resistant state in high grade serous ovarian cancer. We will tackle the emergence of Pt resistance from a global transcriptional reprogramming point of view. Our published and preliminary findings support the hypothesis that Pt resistance emerges from therapy-induced population-level epigenomic and transcriptional reprogramming. Through integrative analysis of epigenomes and transcriptomes of multiple naïve and cisplatin-resistant isogenic cells, we identified resistant-state specific super-enhancers and their target transcription factor networks (TFN). The first aim employs cutting edge genomic mapping and manipulation technologies including single cell-level CRISPR-perturbations followed by transcriptome profiling to identify which TFs and TF-combinations are necessary to reprogram naïve cells into the resistant state. The second aim investigates a novel combinatorial target to achieve synthetic lethality with carboplatin in HGSOC. The findings from this proposal will provide new mechanistic insight into the role of key transcription factor network that govern platinum resistance in ovarian cancer.