Decoding tumor evolution in advanced ovarian cancer: Proteogenomic insights before and after neoadjuvant chemotherapy.
Abstract
e17582 Background: 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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Valentina Iacobelli
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Division of Gynecologic Oncology, Catholic university of the Sacred Heart, Rome, Italy
Marianna Buttarelli
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Division of Gynecologic Oncology, Catholic university of the Sacred Heart, Rome, Italy
Enrica Martinelli
Division of Oncology, Department of Oncology and Hematology, Modena University Hospital, Modena, Italy
Alessia Piermattei
Scientific Directorate, Fondazione Policlinico Universitario "A. Gemelli," IRCCS, Rome, Italy
Giuseppina Raspaglio
Department of Life Sciences and Public Health Section of Gynecology and Obstetrics Catholic University of the Sacred Heart, Rome, Italy
Marta De Donato
Department of Life Sciences and Public Health Section of Gynecology and Obstetrics Catholic University of the Sacred Heart, Rome, Italy
Francesca Sillano
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Division of Gynecologic Oncology, Catholic university of the Sacred Heart, Rome, Italy
Rita Trozzi
Anna Fagotti, MD, PhD, and Rita Trozzi, MD, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy, Università Cattolica del Sacro Cuore, Rome, Italy; Diana Giannarelli, PhD, MSc, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy; and Giovanni Scambia, MD, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy, Università Cattolica del Sacro Cuore, Rome, Italy
Floriana Camarda
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Division of Gynecologic Oncology, Catholic university of the Sacred Heart, Rome, Italy
Tina Pasciuto
Angelo Minucci
Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario "A. Gemelli," IRCCS, Rome, Italy
Luca Mastrantoni
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Luciano Giaco'
Bioinformatics Research Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario "A. Gemelli," IRCCS, Rome, Italy
Giulia Mantini
Bioinformatics Research Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Eduardo Maria Sommella
Department of Pharmacy, University of Salerno, Salerno, Italy
Vicky Caponigro
Pietro Campiglia
Gloria Anderson
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Division of Gynecologic Oncology, Catholic university of the Sacred Heart, Rome, Italy
Giovanni Scambia
Camilla Nero
Gynecologic Oncology Unit, Department of Women’s and Children’s Health Sciences, Fondazione Policlinico Universitario "A. Gemelli," IRCCS, and Catholic University of the Sacred Heart, Rome, Italy