Nuclear enzyme discovery unlocks new paths to combat breast cancer

One of the major challenges in the treatment of the most common subtype of breast cancer (hormone receptor positive, HR+) is the emergence of resistance. In a recent study, Boston Children's Hospital researchers and colleagues have discovered a new driver of resistance in this cancer, introducing a new direction for early diagnosis of the resistant cancer cells, and a possible path to target them.

Many patients treated with the current standard-of-care treatment, CDK4/6-inhibitors, will eventually show resistance to the treatment, which means regrowth of the cancer cells and bad treatment outcomes. Yet, much is still unknown about the genetic drivers behind this resistance. 

In new results published today in Science Advances, a research team co-led by Naama Kanarek, PhD, in the Pathology Department at Boston Children's, and Taru Muranen, PhD, found that an enzyme, Fumarylacetoacetate hydrolase (FAH), thought to be strictly a metabolic enzyme, harbors a second function responsible for a new resistance mechanism. FAH, previously only known for its role in the cell's cytosol, was found in the nucleus of breast cancer cells treated with CDK4/6 inhibitors. The team also discovered the molecular mechanism of FAH resistance; they showed that FAH interacts with the cell fate regulator CDK9 in the nucleus and stimulates its activity, and that inhibiting CDK9 reverses FAH mediated-resistance.

Collectively, these data suggest the possibility of utilizing nuclear FAH as a biomarker of resistance to CDK4/6 inhibitors. Notably, this insight suggests CDK9-inhibition or combination therapy with CDK4/6-inhibitors could be an immediate, actionable clinical approach for mitigating relapse in CDK4/6 inhibitors treated HR+ breast cancer patients.