The immunomodulatory protein Dickkopf-1 (DKK1) defines a non-neuroendocrine subtype of metastatic castration-resistant prostate cancer (mCRPC) with low AR and low PSA expression.

Abstract

5054 Background: Advanced stagemCRPC can manifest AR-signaling independent growth typified by loss of AR and/or PSA expression in the absence of neuroendocrine (NE) features on biopsy. We sought to identify therapeutically relevant biomarkers of this highly resistant prostate cancer subtype. Methods: An unbiased differential gene expression analysis of non-neuroendocrine mCRPC biopsies was carried out comparing patients with ARlow to patients with ARhigh disease in a discovery cohort (SU2C/PCF, 18 pts: 8 ARlow, 10 ARhigh) and validation cohort (Fred Hutchinson, 76 pts: 12 ARlow, 64 ARhigh). The AR and NE status of the biopsies were defined by AR and PSA mRNA expression and gene signatures representative of AR activity and NE lineage. An RNA sequencing-based signature of immune cell subsets was calculated using the Cibersort algorithm. Results: Differential gene expression analysis identified the secreted Wnt antagonist, DKK1, as significantly upregulated in ARlow cases compared to ARhigh cases (11.2 RPKM vs. 0.28 RPKM, p < 0.03) in our discovery cohort and confirmed in our validation cohort (9.2 FPKM vs. 0.99 FPKM, p < 0.001). DKK1 protein was also found to be increased in non-neuroendocrine ARlow relative to ARhigh prostate cancer in vitro cell and organoid models (858 pg/mg total protein vs. 2 pg/mg total protein, p < 0.05) and patient-derived xenografts (28.6 FPKM vs. 0.78 FPKM, p < 0.0001). Consistent with the role of DKK1 as a negative modulator of anti-tumor immunity, patient biopsies with the highest quartile of DKK1 expression showed an RNA signature consistent with lower levels of active NK cells (0.2% vs. 1.8%, p < 0.005), and lower levels of CD8+ T cells (3.7% vs. 9.7%, p< 0.005) compared to those with the lowest quartile of DKK1 expression. Conclusions: DKK1 represents a secreted biomarker that is disproportionately enriched in non-neuroendocrine mCRPCs that lack AR expression. Because DKK1 has been implicated as a suppressor of anti-tumor immunity and is a target of an existing neutralizing antibody, our results support the clinical evaluation of the role of DKK1 blockade in DKK1-positive AR-negative prostate cancer.