Chui Yan Mah

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.

ACSM3 protein levels are elevated in prostate cancer.

Effect of medium chain fatty acids on prostate cancer cells.

Table S1 - list of primers used in the study

Effect of shRNA-mediated knockdown of ACSM3 on prostate cancer growth.

Quantification of medium chain fatty acids by mass spectrometry

Assessment of ACSM1 antibody by immunohistochemistry.

Targeting ACSM1 or ACSM3 does not induce apoptosis of prostate cancer cells.

Quantification of metabolites by mass spectrometry

ACSM1 and ACSM3 are major regulators of the prostate cancer lipidome.