# Project 2: Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $365,099

## Abstract

Our overall objective has been to dissect transcriptional activation by androgen receptor (AR)
and AR splice variants, and mechanisms driving this activity in prostate cancer (PCa) that
becomes resistant to second generation AR targeted therapies including abiraterone and
enzalutamide. We recently found that AR recruits protein phosphatase 1 (PP1α), which can
then dephosphorylate CDK9 and mobilize the P-TEFb complex. In Aim 1 we focus on
identification of the PP1 regulatory protein that interacts with the AR ligand binding domain
(independently of androgen) that mediates this interaction, and on determining whether/how the
AR-V7 splice variant mediates PP1α recruitment and subsequent P-TEFb mobilization. Our
previous and current studies also indicate that phosphorylation of S81 in the AR N-terminal
domain (NTD) plays a major role in driving transcription, and is a hub for a positive feedback
loop that may amplify AR activity at low androgen levels or in the presence of AR antagonists.
Therefore, Aim 2 focuses on identification of coactivator interactions that are directly or indirectly
regulated by S81 phosphorylation, the role of S81 phosphorylation in AR-V7 activity, and the
therapeutic potential of CDK9 inhibitors. Aim 3 then focuses further on AR splice variants. While
AR splice variant homodimers can drive transcription, evidence from others and us indicate that
heterodimers between AR-FL and AR splice variants play a major role. Therefore, we will test
the hypothesis that AR-FL/V7 heterodimers are the major mediators of AR activity in
enzalutamide-resistant PCa models. We then will focus on the role of the LBD in these
heterodimers, and whether they it may still be a therapeutic target. Finally, we will identify
mechanisms in addition to increased expression that appear to be enhancing AR-V7 activity in
enzalutamide-resistant PCa cells. The Specific Aims are 1) Determine the molecular basis for
PP1α recruitment by AR full length and splice variants, 2) Determine the function of AR S81
phosphorylation in driving AR full length and splice variants, 3) Identify mechanisms through
which AR-V7 drives AR activity in ENZ-resistant models.

## Key facts

- **NIH application ID:** 9870889
- **Project number:** 5P01CA163227-07
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Steven P. Balk
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,099
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870889

## Citation

> US National Institutes of Health, RePORTER application 9870889, Project 2: Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance (5P01CA163227-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870889. Licensed CC0.

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