Purpose: Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates appear to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets.
Experimental Design: We generated whole transcriptome RNAseq data from AR-active prostate cancers (ARPC) and SCNPCs from tumors collected at rapid autopsy, and two other NE carcinomas, Merkel Cell Carcinoma (MCC) and small-cell lung cancer (SCLC). We performed cross-tumor comparisons to identify conserved patterns of expression of druggable targets. We tested inhibitors to highly upregulated drug targets in a panel of PC cell lines and in vivo patient-derived xenograft (PDX) models.
Results: We identified BCL2 as highly upregulated in SCNPC compared to ARPC. Inhibitors targeting BCL2 induced apoptotic cell death in SCNPC cell lines at nanomolar concentrations while ARPC cell lines were resistant. Treatment with the BCL2 inhibitor Navitoclax lead to a reduction of growth of SCNPC PDX tumors in vivo, while ARPC PDX models were more resistant. We identified Wee1 as a second druggable target upregulated in SCNPC. Treatment with the combination of Navitoclax and the Wee1 inhibitor AZD-1775 repressed the growth of SCNPC PDX resistant to single agent BCL2 inhibitors.
Conclusions: The combination of BCL2 and Wee1 inhibition presents a novel therapeutic strategy for the treatment of SCNPC.