# Elucidating Synergy of Enzalutamide and Src Kinase Inhibitors in Castration-Resistant Prostate Cancer

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2021 · $33,279

## Abstract

Project Summary
Prostate Cancer (PCa) is the most commonly diagnosed non-skin cancer amongst the American male
population. Therapeutics to treat PCa, which are known as Androgen Deprivation Therapies (ADTs), have
been developed to target the androgen receptor (AR) or androgen synthesis pathways. PCa progresses into
Castration-Resistant Prostate Cancer (CRPC) in the presence of ADTs due to upregulated tyrosine kinase
activity and truncated versions of AR called AR splice variants. While targeting AR with newer second
generation hormonal therapies is at the forefront of treatment of CRPC, combination therapy may be required
to produce a more profound clinical benefit. Previous work from our laboratory has shown that kinase
phosphorylation and activity are elevated in CRPC and have established SRC kinase as a key kinase target
via phosphoproteome-guided multi-omic integration. The objective of the application is to evaluate the synergy
between enzalutamide, a second generation anti-androgen, and SRC kinase inhibitors in prostate cancer
models. The central hypothesis is that enzalutamide paired with SRC kinase inhibitors drives the
downregulation of both AR full-length activity and AR splice variant activity on SRC, resulting in reduced AR-
driven prostate cancer survival and hence greater prostate cancer cell death. Evidence will be provided to
support the hypothesis in the following aims: 1) Elucidate the synergism between enzalutamide and SRC
kinase inhibitors in vitro and in vivo. 2) Determine the binding or phosphorylation between AR and SRC that
contribute to drug synergy. 3) Determine changes in cellular signaling altered by AR and SRC inhibition that
contribute to drug synergy. In vitro experiments for Aim 1 will involve cell viability assays to determine IC50s
of each therapeutic and to determine synergy between SRC kinase inhibitors and enzalutamide via the
Combination Index Equation across a panel of prostate cancer cell lines. In vivo experiments will assess the
synergy between SRC kinase inhibitors and enzalutamide in cell line derived xenografts and previously
established mouse prostate tissue recombination cancer models expressing activated SRC with over-amplified
AR. Experiments for Aim 2 involve immunoassays and targeted phosphoproteomics to analyze changes in
binding or phosphorylation on residues of interest on AR in the presence or absence of SRC kinase inhibitors.
This will involve mass spectrometry to identify key residues phosphorylated on AR in the presence of
enzalutamide followed by site-directed mutagenesis of these residues to determine if the phosphorylation on
AR splice variants contributes to ligand-independent activity of AR. Experiments for Aim 3 involve shotgun
phosphoproteomics and RNA sequencing to assess changes in cellular signaling after administration of our
synergistic combinations. The proposed research is significant because this will provide critical pre-clinical
data that could influence how future clinica...

## Key facts

- **NIH application ID:** 10233117
- **Project number:** 1F31CA261056-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Ralph E White
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,279
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233117

## Citation

> US National Institutes of Health, RePORTER application 10233117, Elucidating Synergy of Enzalutamide and Src Kinase Inhibitors in Castration-Resistant Prostate Cancer (1F31CA261056-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10233117. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*