Abstract
Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor–positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases, no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient–derived models and tumors. We identified an unexpected, noncanonical nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor–resistant HR+ breast cancer.