Does neoadjuvant chemotherapy bias the transcriptomic profile of platinum-sensitive advanced high grade serous ovarian cancer patients towards a resistant phenotype? Findings from a gene expression meta-analysis

Background: Chemoresistance is the key determinant of long-term survival in advanced high-grade serous ovarian cancer (HGSOC). The molecular mechanisms underlying chemoresistance in clinical populations are not clearly known. The present study aimed to analyze the molecular mechanisms promoting chemoresistance, as well as neoadjuvant chemotherapy (NACT) induced sensitive-to-resistant transformation in advanced-HGSOC patients. Methods: RNA-sequencing data from Gene Expression Omnibus (GEO) database was systematically searched and extracted. Pre-chemotherapy (resistant vs sensitive) and chemosensitive (post-chemotherapy vs pre-chemotherapy) subgroup analyses were performed. For each subgroup, differential-gene-expression (DGE) meta-analysis and downstream analysis for pathway enrichment, immune deconvolution, protein-protein fully interconnected network and cancer stem cell expression were performed. In-silico validation in single cell dataset as well as cell line database BioGRID ORCS was performed for proliferation. Results: Three bulk RNA-sequencing datasets (GSE162714, GSE173420, GSE227100) were included in the analysis. Prechemotherapy inherent-resistant samples showed upregulation of inflammation, epithelial-mesenchymal-transition processes, higher stromal proportion in tumors with upregulation of cancer-associated-fibroblasts (CAFs), and CXCL5 overexpression over the sensitive phenotype. On the other hand, exposure to NACT in chemosensitive patients led to upregulation of inflammation, immune evasion, widespread activation of CSC-led proliferation and drug-efflux-pump overexpression, with increased immune and CAF cells in stroma mirroring an inherent-resistance phenotype, implying a sensitive to resistant transformation. Tumor stromal changes and inflammation remained central to resistance overall. Conclusion: Neoadjuvant chemotherapy promotes enrichment of inflammation, immune evasion, EMT and CSC activation thereby promoting chemoresistance and post-NACT sensitive-resistant transformation. Improved understanding of chemoresistance mechanisms will boost interest in stroma-directed therapy in HGSOC to improve survival.