# Identifying prognostic targets in metastatic prostate cancer beyond AR

## TL;DR

The study identifies eight genes that could serve as new therapeutic targets for metastatic prostate cancer based on their strong cell line dependency and poor clinical outcomes.

## Contribution

Combining functional screens with gene expression and clinical data to discover new prostate cancer drug targets beyond the androgen receptor.

## Key findings

- Eight genes (CYC, CYP51A1, DHFR, EBP, KIF15, PPM1D, SQLE, and UMPS) showed strong cell line dependency and worse clinical outcomes.
- Four of these genes (DHFR, EBP, KIF15, and PPM1D) are more highly expressed in neuroendocrine prostate cancer.
- Most of these genes remain targetable post-abiraterone therapy as they are not significantly decreased post-treatment.

## Abstract

Genome‐wide screens using CRISPR/RNAi can identify new therapeutic vulnerabilities in prostate cancer. In this study, we combine DepMap functional screen data with a large gene expression database (N = 1012) and clinical outcomes to identify potentially druggable targets. Eight genes (CYC, CYP51A1, DHFR, EBP, KIF15, PPM1D, SQLE, and UMPS) demonstrated strong dependency in cell lines and were also associated with worse prognosis clinically, representing potential therapeutic targets in metastatic prostate cancer. Four of these (DHFR, EBP, KIF15, and PPM1D) demonstrated higher expression in neuroendocrine prostate cancer. Furthermore, all but one (KIF15) were not significantly decreased from pretreatment to posttreatment, suggesting that they may remain targetable postabiraterone therapy. All eight genes showed evidence of protein expression in prostate cancers or cell lines. These potentially druggable targets associated with prostate cancer cell line dependency and worse clinical outcomes have also demonstrated literature support as potential targets, supporting further research into their potential clinical relevance as therapeutic targets in prostate cancer.

Genome‐wide functional screens combined with a large gene expression database and clinical outcomes can identify new therapeutic vulnerabilities in prostate cancer. Eight potentially druggable targets demonstrated strong dependency in cell lines, were associated with worse prognosis clinically, and showed evidence of protein expression in prostate cancers or cell lines, representing potential therapeutic targets.