# Mechanisms of Therapeutic Resistance in Prostate Cancer

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2022 · —

## Abstract

Background: Enhancer of zeste homolog 2 (EZH2) is a component of Polycomb Repressive Complex 2 (PRC2)
and a key epigenetic regulator. EZH2 is overexpressed in metastatic prostate cancer (PCa), and its activity is
critical for PCa progression and therapeutic resistance. Inhibition of EZH2 has become a promising cancer
treatment option. Studies showed that agents depleting EZH2 protein had better antitumor efficacy than those
only inhibiting its methyltransferase activity, suggesting that combination therapy may lead to more effective by
inhibiting both EZH2 activity and protein turnover. SRC tyrosine kinase is upregulated in castration resistant
prostate cancer (CRPC), and plays a driver role in PCa progression. Despite a promising improvement in Phase
II clinical trials, combination therapy using docetaxel and the SRC inhibitor dasatinib failed in a later large
randomized phase III trial- suggesting that patient selection and new drug combination are critical for
development of effective treatment.
Hypothesis and Aims: Our preliminary study showed that SRC can induce EZH2 tyrosine phosphorylation.
The phosphorylation mutant compromised EZH2 stability and activity. The mutant failed to interact with PRC2
associated proteins and de-repressed EZH2-regulated genes. Furthermore, combination treatment of EZH2 and
SRC inhibitors displayed synergistic growth inhibitory effects. We hypothesize that tyrosine phosphorylation of
EZH2 is critical for its oncogenic activity and contributes to castration resistance; and simultaneous inhibition of
EZH2 and its upstream kinases may attenuate CRPC growth more effectively. Specific Aims: 1) Delineate the
mechanisms by which EZH2 activity is regulated by tyrosine phosphorylation. 2) Determine the functional
significance of EZH2 phosphorylation in resistance to androgen deprivation therapy in preclinical models.
Study Design: We will study how EZH2 tyrosine phosphorylation modulates its stability and functional
interaction with its known partners, and identify phosphorylation-dependent interacting partners using proteomic
approaches. We will also perform ChIP-seq to define the signature of genes regulated by phosphorylated EZH2
using the anti-pEZH2 phospho-specific antibody we developed. We will examine whether EZH2 phosphorylation
mutation or tyrosine kinase inhibitors can sensitize CRPC to EZH2 inhibitors in xenograft models. Successful
completion of this project will provide new mechanistic insights into castration resistance and lead to the
development of new effective combination therapy to circumvent therapeutic resistance in prostate cancer
treatment, and optimally reduce or delay lethality in Veterans who suffer from prostate cancer.

## Key facts

- **NIH application ID:** 10474271
- **Project number:** 5I01BX004160-05
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Yun Qiu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474271

## Citation

> US National Institutes of Health, RePORTER application 10474271, Mechanisms of Therapeutic Resistance in Prostate Cancer (5I01BX004160-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10474271. Licensed CC0.

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