CLDN6 Expression Plasticity in Ovarian Cancer: Insights into Therapeutic Optimization for CLDN6-Targeted...

Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy, characterized by extensive tumor heterogeneity that contributes to treatment resistance and high recurrence rates. Recently, we developed SAIL66, a CLDN6-targeting T-cell engager currently in clinical evaluation for CLDN6-positive solid cancers, including EOC. Whereas CLDN6 is considered an attractive target for cancer therapy due to its cancer specificity, its biology remains poorly understood. In this study, we investigated the biological characteristics of CLDN6-positive EOC to identify its significance as a therapeutic target for ovarian cancer treatment. We demonstrated heterogeneous CLDN6 expression in xenograft and clinical tumors. In vitro-cultured ovarian cancer cell lines showed reversible changes in CLDN6 expression depending on cell density, accompanied by alterations in epithelial-mesenchymal transition (EMT)-related and stemness-related genes. Spatial transcriptomic analysis of clinical specimens revealed that CLDN6-positive areas formed both solid regions and dispersed small clusters within the same tumors, with differential expression of EMT-related and cell matrix remodeling genes between these areas, consistent with our in vitro observations at varying cell densities. Furthermore, carboplatin treatment increased CLDN6 expression, accompanied by changes in EMT-related genes. Leveraging these biological characteristics of CLDN6, we discovered that significant tumor regression was observed in mice treated with SAIL66 following carboplatin pretreatment. Post-carboplatin analysis revealed increased CLDN6 expression, EMT-related gene changes, and enhanced T-cell infiltration, which were associated with the synergistic effect of SAIL66. Our study provides insights into the biology and plasticity of CLDN6-positive cells in EOC heterogeneity and highlights the clinical significance of CLDN6-targeting therapies for ovarian cancer treatment.

CLDN6-positive ovarian cancer cells exhibit remarkable plasticity influenced by microenvironmental factors and chemotherapy, providing critical insights for understanding the biology of ovarian cancer progression and optimizing CLDN6-targeting therapy.