A non-canonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer II

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, non-catalytic 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.