A Novel Platinum-Resistance-related Gene Signature in Ovarian Cancer: Identification and Patient-derived Organoids Verification.

Abstract

Background: Platinum-based chemotherapy resistance is one of the main contributors to the mortality of Ovarian Cancer (OC). It is believed that sensitive biomarkers for identifying the population that is platinum-resistant are urgently needed. This study aims to develop a platinum-resistance gene-based signature to predict OC patients' responses to platinum drugs as well as survival outcomes.

Methods: A platinum-resistance-related gene model was built by bioinformatics analysis. Then, its predictive power was internally validated. Continually, a nomogram was constructed to confirm the model's predictive ability. Afterward, GSEA was used to explore our model's potential functions. The ESTIMATE, CIBERSORT, TIMER, and ssGSEA were applied to estimate immune conditions. Then, somatic mutation and drug sensitivity were also analyzed. Finally, to gain insights into the roles of targeted genes in drug sensitivity, patient-derived tumor organoids (PDOs) validation was performed.

Results: Nine platinum-resistance-related genes, including SLC22A2, TAP1, PC, MCM3, GTF2H2, FXYD5, SUPT6H, IGKC, and MATN2, were anchored to build the predictive model, which was well internally validated. Subsequently, GSEA unveiled that our model genes enriched in the Hedgehog signaling pathway. The predictive signature was associated with immune checkpoint inhibitors such as PD-1, PD-L1, and CTLA4, guiding immunotherapy applications for OC patients. Drugs such as dasatinib, midostaurin, metformin, MK-2206, and mitomycin C might also benefit OC patients with different risk scores. PDOs showed patients with high-risk scores were more resistant to cisplatin than patients with low-risk scores.

Conclusion: The platinum-resistance-related gene signature (SLC22A2, TAP1, PC, MCM3, GTF2H2, FXYD5, SUPT6H, IGKC, and MATN2) is valuable for prognosis prediction and guidance of treatment choices for OC patients.