ESR1 activating mutations confer metabolic vulnerabilities in ER+ breast cancer

Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancer. Point mutations in the ligand-binding domain of the gene encoding the estrogen receptor (ESR1) are rare in naïve ER+ breast cancer while becoming common in the ET-resistant setting. Here, we found that ESR1 mutations expose breast cancers to critical vulnerabilities related to lipid metabolism. Particularly, ESR1 mutations that induce constitutive ER activation drove aberrant lipid biogenesis and lipid upload in parallel with increased expression of the acyl-CoA synthetase long-chain family member 4 (ACSL4), which has a crucial role in fatty acid activation and has been shown to correlate with increased ferroptosis susceptibility. While ER+ breast cancer cells displayed ferroptosis resistance, the presence of ESR1 mutations rendered tumor cells sensitive to ferroptosis induction. Importantly, ferroptosis inducers potentiated the effects of the selective estrogen receptor degraders fulvestrant and elacestrant, which are the standard of care for breast cancers carrying ESR1 mutations. These findings, validated both in preclinical models and in patient-derived material, identify a combinatory therapeutic approach in the setting of ET resistance and establish ACSL4 as an important biomarker to recognize ER+ breast cancers susceptible to ferroptosis induction.