ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development

Haiqing He,Hui Xue,Xinpei Ci,Yu Wang,Rebecca Wu,Jun Hao,Xiaokun Zhao,Xin Dong,Sifeng Qu,Colin Collins,Dong Lin,Stephen Yiu Chuen Choi,Yuzhuo Wang,Mingchen Shi,Yong Wang

doi:10.1038/s41391-021-00322-7

Abstract

BackgroundAndrogen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development.MethodsWe have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies.ResultsZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway.ConclusionUsing our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.

Highlights

Androgen deprivation therapy (ADT) remains the first-line treatment for patients with locally advanced and metastatic prostate cancer (PCa) [1]
We have previously developed a series of patient-derived xenograft (PDX) models derived from patient hormone-naïve PCa (HNPC) tissues
Since tumor samples can be collected at different time points throughout this process, these PDX models allow us to carry out longitudinal analyses of castration-resistant prostate cancer (CRPC) development and offer a unique tool for tracing early molecular changes

Summary

Introduction

Androgen deprivation therapy (ADT) remains the first-line treatment for patients with locally advanced and metastatic prostate cancer (PCa) [1]. The discovery that most CRPCs are still dependent on androgen and androgen receptor (AR) signaling led to the development of several new androgen receptor pathway inhibitors (ARPIs) such as abiraterone, enzalutamide and apalutamide [2,3,4]. While these next-generation ARPIs can effectively reduce symptoms and prolong life, metastatic CRPC (mCRPC) remains incurable as resistance to these ARPIs frequently emerges. While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development

Methods

Results

Conclusion