The development of second-generation androgen receptor (AR) antagonists, such as enzalutamide, considerably improved oncological outcomes in patients with prostate cancer, but therapy resistance hampers the efficacy of these therapeutics. In a study published in Oncogene, metabolic profiling was carried out in different prostate cancer models to characterize the metabolic mechanisms underlying enzalutamide resistance.
A metabolomic analysis of enzalutamide-sensitive (EnzS) cells (LNCaP cells) showed that treatment with enzalutamide induced an alteration to glutamine metabolism. Consistently with a role of glutamine pathways in the regulation of antioxidant levels, an increase in reactive oxygen species (ROS) was observed in AR-expressing but not AR-null cells treated with enzalutamide, indicating that this enzalutamide-dependent ROS activation was mediated by AR. In freshly extirpated primary prostate tumours (which are mostly sensitive to enzalutamide) cultured ex vivo, ROS activation was observed under enzalutamide treatment. Higher basal ROS levels and increased ROS activation in response to oxidizing agents were observed in fresh tumours from patients with castration-resistant prostate cancer (CRPC) compared with primary treatment-naive tumours, supporting the idea that oxidative stress levels positively correlate with disease progression and anti-androgen treatment. Results from steady-state metabolic profiling in six matched pairs of EnzS and enzalutamide-resistant (EnzR) cell lines showed that amino acid metabolism was the most frequently altered pathway in EnzR cells and that glutamine metabolism was upregulated in these cells. Notably, tumour samples from patients with CRPC had higher levels of glutamine than treatment-naive tumours. Results from proliferation assays showed that glutamine deprivation (or glutaminase inhibition) inhibited proliferation in EnzR but not EnzS cells, indicating that EnzR cells are sensitive to glutamine blockade. Treatment with antioxidants rescued the glutamine blockade-mediated proliferation inhibition in EnzR cells, indicating that this effect is mediated by ROS. These results were confirmed in vivo, using EnzR xenografts.
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