Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKC\u03b21

James E Melnyk,Kevan M Shokat,Veronica Steri,Byron Hann,Y Christina Hwang,Felix Y Feng,John D Gordan,Hao G Nguyen

doi:10.1038/s41388-022-02179-z

Abstract

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.

Highlights

Androgen receptor signaling inhibitors (ARSi) are currently the primary treatment regimen for advanced prostate cancer
We hypothesized that PKCβ1 is present at the androgen receptor (AR) genomic locus during low-androgen conditions, promoting transcription and increasing total AR transcript levels by phosphorylating histone H3T6 (Fig. 1A)
We propose PKCβ1 as an important component of the low-androgen stress response that upregulates AR gene expression and increases full-length AR and AR-V7 protein levels during AR antagonism

Summary

Introduction

Androgen receptor signaling inhibitors (ARSi) are currently the primary treatment regimen for advanced prostate cancer. These therapies work either by directly antagonizing the AR at its ligandbinding domain (LBD) or by inhibiting androgen synthesis. Such treatments are generally initially successful, but many patients eventually relapse and develop lethal, metastatic castrationresistant prostate cancer (CRPC), which thrives even in a reduced-hormone environment [1]. ARV7 is a constitutively active, androgen-independent transcription factor that lacks its LBD but retains its DNA-binding domain and is able to circumvent the actions of current anti-androgen therapies that target the LBD [5–7]. While anti-androgen therapies block activation of full-length AR, AR-V7 which is produced lacks the LBD resulting in an undruggable isoform of the druggable AR oncogene [5, 7], and has established an unmet need for novel therapeutic approaches to target AR-V7

Methods

Results

Conclusion