Multi-omic profiling reveals metabolic vulnerabilities in enzalutamide resistant prostate cancer

Abstract Resistance to the androgen receptor inhibitor enzalutamide (ENZ) is a major barrier to durable control of advanced prostate cancer. Given the central role of metabolic reprogramming in tumour survival under therapeutic stress, we investigated whether ENZ resistance is associated with adaptive metabolic rewiring that promotes stress tolerance and evasion of cell death. Multi-omic profiling of ENZ-sensitive (C4-2B and V16D) and ENZ-resistant (MR49F) cells revealed extensive metabolic reprogramming, with lipid metabolism emerging as a dominant axis. ENZ-resistant cells displayed depletion of long-chain polyunsaturated fatty acids (PUFAs) and increased resistance to lipid peroxidation and ferroptosis. Restoring PUFA availability or activating lipid regulatory pathways via treatment with a liver X receptor (LXR) agonist re-sensitised resistant cells to ferroptotic cell death. In parallel, nitrogen metabolism was altered in ENZ-resistant cells, including increased carbamoyl phosphate synthetase 1 (CPS1) and resistance to ammonium exposure. Treatment with the CPS1 inhibitor H3B-120 reduced proliferation of MR49F cells and increased their sensitivity to ammonium stress. Together, these findings identify coordinated lipid and nitrogen remodelling as targetable metabolic adaptations that support resistance to cellular stress and death in ENZ-resistant prostate cancer cells.