# Metabolic alterations contributing to enzalutamide resistance in prostate cancer

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $40,370

## Abstract

Project Summary/Abstract
Resistance to the androgen receptor (AR) antagonist enzalutamide remains a major cause of mortality among
prostate cancer (PCa) patients. Thus, it is crucial that we identify which patients will become resistant and
define the mechanism by which resistance develops. Because metabolic alterations are critical for determining
whether cancer cells will resist stress and proliferate, this proposal aims to define the metabolic program that
drives enzalutamide resistance. Comparative metabolic studies in six paired enzalutamide-sensitive (EnzS)
and enzalutamide-resistant (EnzR) PCa cell lines indicate that EnzR cells have enhanced glutamine
metabolism and are more glutamine dependent. This is supported by previous data showing that AR promotes
glutamine uptake and glutaminolysis. Further characterization indicates that resistant cells have increased
oxidative stress, and the growth of EnzR cells is promoted by antioxidants, such as glutathione (GSH). The
role of oxidative stress is corroborated by data suggesting that enzalutamide inhibits antioxidants and induces
reactive oxygen species (ROS). Given that an important role of glutamine is to generate antioxidants, we
propose that enhanced glutamine metabolism drives enzalutamide resistance in prostate cancer by
upregulating antioxidant programs to tolerate increased oxidative stress, and this resistance mechanism is
targetable. This proposal will test this hypothesis through the use of unbiased steady-state and metabolic flux
techniques in EnzS and EnzR cells in vitro, mouse xenografts in vivo, and patient tumors. The link between
metabolic dependencies and ROS will be further characterized by fluorescence microscopy and enzymatic
activity approaches. RNAi, CRISPR-Cas9, and lentiviral-mediated overexpression of glutaminase (GLS), a
critical enzyme in glutaminolysis, and glutamate-cysteine ligase, a rate-limiting enzyme for GSH synthesis, will
be used to establish the necessity and sufficiency of these alterations for driving resistance. Known inhibitors
of these enzymes will be used in vitro, in vivo, and in patient-derived tumors cultured ex vivo to determine
whether these therapeutic strategies will be potentially efficacious in the treatment of EnzR PCa. This
proposed research will provide the understanding of mechanisms that enable the evolution of enzalutamide
resistance and allow for the development of therapies leading to more durable responses to enzalutamide in
the clinic.

## Key facts

- **NIH application ID:** 10236294
- **Project number:** 5F31CA243276-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Eliot Blatt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,370
- **Award type:** 5
- **Project period:** 2020-08-03 → 2023-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236294

## Citation

> US National Institutes of Health, RePORTER application 10236294, Metabolic alterations contributing to enzalutamide resistance in prostate cancer (5F31CA243276-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10236294. Licensed CC0.

---

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