Researchers co-led by Naama Kanarek of Boston Children's Hospital and Taru Muranen identified a previously unrecognized nuclear function of fumarylacetoacetate hydrolase (FAH) that drives resistance to CDK4/6 inhibitors in hormone receptor-positive (HR+) breast cancer, according to a study published September 30, 2026 in Science Advances.
CDK4/6 inhibitors are standard treatments for HR+ breast cancer, but resistance commonly develops and is not always explained by known genomic alterations. Using breast cancer models and patient tumor samples, the researchers found that CDK4/6 inhibition caused FAH, an enzyme best known for its role in tyrosine metabolism in the cytosol, to relocate to the nucleus.
In the nucleus, FAH interacted with cyclin-dependent kinase 9 (CDK9) and increased its activity, allowing cancer cells to survive despite CDK4/6 blockade. Inhibiting CDK9 reversed FAH-mediated resistance in experimental models, identifying CDK9 as a potential therapeutic vulnerability.
The researchers also reported enrichment of nuclear FAH in tumors from patients who had relapsed after CDK4/6 inhibitor treatment, suggesting that nuclear FAH could potentially serve as a biomarker of resistance.