Identification of Therapeutic Vulnerabilities in Small-cell Neuroendocrine Prostate Cancer
Alexandra N Corella1,2, Ma Victoria Andrea Cabiliza Ordonio1,2, Ilsa Coleman1,2
1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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.
Insights
Small-cell neuroendocrine prostate cancer (SCNPC) is aggressive and hard to treat. Targeting BCL2 and Wee1 shows promise for new SCNPC therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Small-cell neuroendocrine prostate cancer (SCNPC) is an aggressive malignancy with increasing incidence, often developing resistance to androgen receptor antagonists.
- Limited treatment options and few available model systems hinder the development of new therapeutic strategies for SCNPC.
Purpose of the Study:
- To identify commonalities between SCNPC and other aggressive neuroendocrine carcinomas to discover potential therapeutic targets.
- To evaluate druggable targets by comparing gene expression patterns across different neuroendocrine tumor types.
Main Methods:
- Whole transcriptome RNA-sequencing was performed on SCNPC, androgen receptor-positive prostate cancer (ARPC), Merkel cell carcinoma (MCC), and small-cell lung cancer.
- Cross-tumor expression comparisons identified upregulated druggable targets in SCNPC.
- Inhibitors of identified targets were tested in SCNPC cell lines and patient-derived xenograft (PDX) models.
Main Results:
- BCL2 was significantly upregulated in SCNPC compared to ARPC. BCL2 inhibitors induced apoptosis in SCNPC cell lines but not ARPC.
- Navitoclax (a BCL2 inhibitor) reduced SCNPC PDX tumor growth, while ARPC PDX models showed resistance.
- Wee1 was identified as another upregulated target. Combination therapy with navitoclax and a Wee1 inhibitor (AZD-1775) repressed SCNPC PDX growth, including in tumors resistant to single-agent BCL2 inhibition.
Conclusions:
- BCL2 and Wee1 are promising therapeutic targets for SCNPC.
- Combined inhibition of BCL2 and Wee1 represents a novel and effective therapeutic strategy for SCNPC, demonstrating efficacy even in resistant models.
