A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer.

Nuclear FAH, a tyrosine degradation enzyme, drives CDK4/6 inhibitor resistance in HR+ breast cancer, with 80% of relapsed tumors showing its enrichment.

• Why it matters: Overcoming resistance to CDK4/6 inhibitors is critical, as many patients relapse without clear genetic causes, highlighting the need to understand non-genetic mechanisms.
• What they did: Researchers used breast cancer patient-derived models and tumor samples to investigate resistance, discovering that FAH relocates to the nucleus and interacts with CDK9 to promote resistance.
• The result: Inhibiting CDK9 reversed FAH-mediated resistance, suggesting nuclear FAH as a biomarker and CDK9 as a potential therapeutic target in resistant HR+ breast cancer.