Decoding tumor evolution in advanced ovarian cancer: Proteogenomic insights before and after neoadjuvant chemotherapy

e17582Background: Platinum-based neoadjuvant chemotherapy (NACT) is a cornerstone in advanced ovarian cancer (OC) treatment. However, biomarkers predictive of response and the mechanisms underlying chemoresistance remain poorly defined. The PROGENITOR study aimed to (1) identify biomarkers associated with treatment response, as measured by Chemotherapy Response Score (CRS) and platinum-free interval (PFI), and (2) elucidate pathways driving chemoresistance and tumor adaptation. Methods: Tumor samples from 39 OC patients were analyzed pre- (T0) and post-NACT (T1) using RNA sequencing and liquid chromatography-mass spectrometry. Differentially expressed genes (DEGs) and proteins (DEPs) were identified, and transcriptomic-proteomic integration was performed. Deconvolution analysis, using xCell tool, evaluated tumor microenvironment dynamics, stratified by CRS and PFI. Genomic alterations were also correlated with transcriptomic and proteomic changes. Results: Longitudinal analysis revealed significant downregulation of PKMYT1, CDK1, and UBE2C at T1, suggesting impaired cell cycle progression and the potential induction of a quiescent state, contributing to chemoresistance mechanisms, as observed in CCNE1-amplified tumors. Deconvolution analysis revealed notable shifts in the tumor microenvironment post-NACT. Cancer-associated fibroblasts (CAFs) and stromal scores increased significantly in OC patients with suboptimal response (CRS 1–2), highlighting their role in chemoresistance through extracellular matrix remodeling. Additionally, immune cell populations showed significant alterations, including reduced T-cell and natural killer cell composition, along with a decline in dendritic cells, suggesting impaired antitumor immunity. These immune-stromal alterations were more pronounced in patients with poor PFI (<6 months). Conclusions: This study suggests dependency on PKMYT1 for CDK1 inhibition and a role in chemoresistance, particularly in CCNE1-amplified tumors. The integration of multi-omics and deconvolution analysis underscores the critical roles of cell cycle dysregulation, stromal activation, and immune suppression in shaping tumor evolution under NACT. These findings provide a foundation for biomarker-driven therapeutic strategies targeting cell-cycle machinery.