Identification of Therapeutic Vulnerabilities in Small-cell Neuroendocrine Prostate Cancer

Clin Cancer Res. 2020 Apr 1;26(7):1667-1677. doi: 10.1158/1078-0432.CCR-19-0775. Epub 2019 Dec 5.

Abstract

Purpose: Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem 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 RNA-sequencing data from AR-active prostate cancers (ARPCs) and SCNPCs from tumors collected at rapid autopsy and two other neuroendocrine carcinomas, Merkel cell carcinoma (MCC), and small-cell lung cancer. 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 prostate cancer cell lines and in vivo patient-derived xenograft (PDX) models.

Results: We identified BCL2 as highly upregulated in SCNPC compared with 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 leads to a reduction of growth of SCNPC PDX tumors in vivo, whereas 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Carcinoma, Neuroendocrine / drug therapy
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / metabolism
  • Carcinoma, Neuroendocrine / pathology*
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / metabolism
  • Carcinoma, Small Cell / pathology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • BCL2 protein, human
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Protein-Tyrosine Kinases
  • WEE1 protein, human