Anti-androgen therapy induces transcriptomic reprogramming in metastatic castration-resistant prostate cancer in a murine model

Despite recent development of next-generation androgen receptor (AR) antagonists, metastatic castration-resistant prostate cancer (CRPC) remains incurable and requires deeper understanding through studies in suitable animal models. Prostate-specific deletion of Pten and Smad4 in mice recapitulated the disease progression of human prostate adenocarcinoma, including metastasis to lymph nodes and lung. Moreover, Pten/Smad4 tumors fostered an immunosuppressive microenvironment dominated by myeloid-derived suppressor cells (MDSCs). However, the response of Pten/Smad4 tumors to androgen deprivation and anti-androgen therapies has not been described. Here, we report that the combination of surgical castration and enzalutamide treatment in Pten/Smad4 mice slowed down the tumor growth and prolonged the median survival of the mice for 8 weeks. Treatment-naive and castration-resistant primary tumors exhibited comparable levels of immune infiltrations with the exception of reduced monocytic MDSCs in CRPC. RNA profiling of treatment-naive and castration-resistant primary tumors revealed largely preserved transcriptome with modest expressional alterations of collagenrelated and immune-related genes, among which C-C chemokine receptor type 2 (Ccr2) downregulation and predicted negative activation in CRPC was consistent with reduced monocytic MDSC infiltration. Importantly, significant transcriptomic reprograming was observed in lung metastatic CRPC compared with primary CRPC and enriched for immune-related and coagulation-related pathways. At the individual gene level, we validated the expression changes of some of the most upregulated (Cd36, Bmp5, Bmp6, Etv5, Prex2, Ptprb, Egfl6, Itga8 and Cxcl12) and downregulated genes (Cxcl9 and Adamts5). Together, this study uncovers the inherent activity of Pten/Smad4 tumors to progress to CRPC and highlights potentially targetable transcriptomic signatures associated with CRPC metastasis.

Automated summary

Despite advancements in AR antagonists, CRPC remains incurable and requires further study in animal models. Prostate-specific deletion of Pten and Smad4 in mice mimics human prostate adenocarcinoma, with Pten/Smad4 tumors promoting an immunosuppressive microenvironment. Combination therapy of surgical castration and enzalutamide in Pten/Smad4 mice slows tumor growth and prolongs survival. RNA profiling reveals transcriptomic alterations in CRPC, particularly related to immune-related and coagulation-related pathways in lung metastatic CRPC.