Platinum-based chemotherapy has long been foundational in the management of ovarian cancer, yet nearly 70% of patients eventually relapse and develop platinum resistance—a clinical turning point associated with limited therapeutic options and poor survival.

A review published in Genes & Diseases by researchers from Central South University, Changsha Medical University, and Dali University provides an integrated overview of the diverse biological mechanisms that underlie platinum-resistant ovarian cancer (PROC) and examines emerging therapeutic strategies with clinical promise.

The authors outline how platinum resistance arises from multilayered alterations within tumor cells and their microenvironment. Key contributors include genomic and epigenetic changes, such as TP53 mutations, CCNE1 amplification, BRCA1/2 restoration, and aberrant methylation patterns. Pharmacological resistance mechanisms—notably reduced platinum uptake, increased efflux, and detoxification by glutathione and metallothioneins—further decrease intracellular drug accumulation.

A major focus of the review is the rewiring of DNA damage repair. By enhancing homologous recombination, nucleotide excision repair, and translesion synthesis, PROC cells effectively counter platinum-induced DNA lesions. Complementing these pathways, metabolic reprogramming—including increased glycolysis, fatty acid oxidation, and glutamine–glutathione metabolism—supports cell survival under chemotherapeutic stress.

Beyond tumor-intrinsic changes, the authors emphasize the role of the tumor microenvironment, where cancer-associated fibroblasts, adipocytes, macrophages, mesothelial cells, and ovarian cancer stem cells cooperate to enforce immune suppression, enhance cancer cell fitness, and drive resistance. Concurrently, disruptions in programmed cell death pathways—such as reduced apoptosis and ferroptosis, along with elevated autophagy—further sustain chemoresistance.
Importantly, the review highlights an expanding therapeutic landscape for PROC. Antibody–drug conjugates (ADCs), including mirvetuximab soravtansine (FRα), trastuzumab deruxtecan (HER2), and CDH6-targeting raludotatug deruxtecan, demonstrate meaningful activity in clinical trials. Additional promising strategies include immune-based therapies, WEE1 inhibition for CCNE1-amplified tumors, PI3K inhibitors, GSH-targeting drugs, platinum (IV) prodrug nanotherapeutics, and RNAi-based approaches.

Recognizing the limitations of current diagnostic and treatment frameworks, the authors advocate for a shift toward integrated multi-omics profiling, functional drug testing platforms such as zebrafish and 3D spheroid models, and biomarker-guided patient stratification to enable personalized management of PROC. They emphasize that redefining platinum resistance—beyond static clinical categories—will be essential for improving clinical decision-making and optimizing therapeutic outcomes.

Overall, this comprehensive synthesis provides an essential framework for researchers and clinicians working to overcome one of the most urgent unmet needs in gynecologic oncology—restoring treatment sensitivity and improving survival for women facing platinum-resistant ovarian cancer.

Reference
Title of Original Paper: Platinum-resistant ovarian cancer: From mechanisms to treatment strategies

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101801
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