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bioRxiv · 10.1101/2025.11.18.689150

CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer

Liu, G.·Wang, S.·Duong, L.·Zeng, Z.·Yang, J.·Zhao, Y.·Rahmy, S.·Feng, S.·Arce, A.·Jia, L.·Wan, J.·Cheng, L.·Lu, X.
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Abstract

PurposeBasal-like (also known as double-negative) prostate cancers are aggressive tumors that lack effective targeted therapies. We aimed to delineate the role of CDH3 (P-cadherin) in basal-like prostate cancer and evaluate CDH3-directed therapeutic strategies. MethodsWe integrated genetically engineered mouse models (GEMMs) of prostate cancer, bulk and single-cell transcriptomic analyses, and a suite of in vitro and in vivo experiments. CDH3 expression and associated signaling pathways were examined in Pten/Apc double-knockout mouse prostates and human datasets. Functional studies included antibody-drug conjugate (ADC) cytotoxicity assays and the development of chimeric antigen receptor (CAR) T cells targeting CDH3, tested in prostate cancer cell lines and xenograft models. ResultsPten/Apc double deletion in prostate GEMMs led to highly aggressive tumors with markedly elevated CDH3 expression and enrichment of non-canonical WNT signaling components. Transcriptomic analyses of patient-derived prostate tumors confirmed that CDH3 is significantly upregulated in basal-like prostate cancer subtypes relative to luminal subtypes. Single-cell RNA sequencing revealed CDH3 expression predominantly in basal epithelial cells. Mechanistically, we found that active YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. Targeting CDH3 with a CDH3-specific ADC induced potent, antigen-dependent killing of CDH3 prostate cancer cells in vitro and significantly suppressed tumor growth in in vivo metastatic prostate cancer models. Likewise, CDH3-targeted CAR T cells specifically recognized and lysed CDH3-expressing prostate tumor cells while sparing CDH3-negative cells, leading to tumor regression and improved survival in mouse models, especially when combined with PD-1 checkpoint blockade. ConclusionsCDH3 is a key marker and functional driver of basal-like prostate cancer. Therapeutic strategies leveraging CDH3, including ADCs and CAR T cells, demonstrate strong preclinical efficacy, supporting the development of CDH3-targeted treatments to overcome resistance in aggressive prostate cancer.

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Liu, G., Wang, S., Duong, L., Zeng, Z., Yang, J., Zhao, Y., Rahmy, S., Feng, S., Arce, A., Jia, L., Wan, J., Cheng, L., Lu, X.. 2025-11-19. CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer. https://doi.org/10.1101/2025.11.18.689150

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