Metabolic rewiring that protects against ferroptosis underlies resistance to CDK4/6 inhibition in prostate cancer

Abstract The G1/S phase transition of the cell cycle, controlled by cyclin-dependent kinase 4/6 (CDK4/6), is frequently deregulated in metastatic prostate cancers, establishing a rationale for CDK4/6 inhibition as a therapeutic strategy. However, clinical trials in prostate cancer have shown limited efficacy due to resistance mechanisms that remain unclear. In this study, we demonstrate that acquired resistance to the CDK4/6 inhibitor ribociclib in prostate cancer cells is driven by enhanced mitochondrial metabolic activity and increased dependence on fatty acid β-oxidation for energy production through the TCA cycle. Metabolic rewiring increased expression of ferroptosis regulators that drive an acquired protection from accumulation of polyunsaturated phospholipids, lipid peroxidation and ferroptosis mediated via GPX4. Exogenous PUFAs enhanced sensitivity to GPX4 inhibition in resistant cells, which was abrogated by exogenous MUFAs. These findings reveal novel mechanisms of resistance to cell cycle blockade and highlight potential adaptations for intervention with therapeutics that induce cell cycle arrest in prostate cancer.