# TAS3681, an androgen receptor antagonist, prevents drug resistance driven by aberrant androgen receptor signaling in prostate cancer

## TL;DR

TAS3681 is a new drug that fights prostate cancer by blocking harmful androgen receptor activity that causes resistance to existing treatments.

## Contribution

TAS3681 is a novel AR pure antagonist that inhibits AR signaling and resistance mechanisms in prostate cancer.

## Key findings

- TAS3681 inhibits AR transcriptional activity and reduces AR-FL and AR-Vs protein levels in resistant cancer cells.
- TAS3681 shows strong antitumor efficacy in AR-V7-positive xenograft models and suppresses mutant ARs linked to drug resistance.
- TAS3681 downregulates AR expression in AR-overexpressing cells and blocks constitutively active AR-V7.

## Abstract

Second‐generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration‐resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR‐splice variants (AR‐Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR‐full length (AR‐FL) and AR‐Vs. TAS3681 reduced the protein levels of AR‐FL and AR‐Vs including AR‐V7 in enzalutamide‐resistant cells (SAS MDV No. 3‐14), in vitro and in vivo, showing strong antitumor efficacy in an AR‐V7‐positive xenograft model. In AR‐overexpressing VCaP (prostate cancer) cells, conversely to enzalutamide, TAS3681 effectively suppressed cell proliferation and downregulated AR expression. Importantly, TAS3681 blocked the transcriptional activity of various mutant ARs, including mutations F877L/T878A and H875Y/T878A, which confer resistance to enzalutamide, and V716M and H875Y mutations, which confer resistance to darolutamide. Our results demonstrate that TAS3681 suppresses the reactivation of AR signaling, which causes resistance to ARSIs, via a newly identified mechanism of action. Therefore, TAS3681 could be a new therapeutic option for CRPC treatment.

The androgen receptor (AR) antagonist TAS3681 is effective against AR mutations, which leads to agonistic activity of AR signal inhibitors, and had an antitumor effect in an AR‐splice variant 7 (AR‐V7)‐positive enzalutamide‐resistant xenograft model. TAS3681 suppresses aberrant AR activation, including AR overexpression and expression of constitutively active nuclear‐localized AR‐V7, via downregulation of AR and AR‐V7.