A new study has identified a potential biomarker that could predict resistance to CDK4/6 inhibitors in hormone receptor-positive breast cancer. Researchers found that the nuclear localization of the enzyme fumarylacetoacetate hydrolase (FAH) may indicate resistance to these inhibitors, which are a standard treatment for metastatic HR-positive breast cancer.
The research, published in Science Advances, highlights the need for better predictive biomarkers, as around 20% of patients are resistant to CDK4/6 inhibitors from the start, and most responders eventually develop resistance.
Uncovering a New Resistance Mechanism
The team, led by Jenny Högström, PhD, analyzed amino acid pathways in breast cancer patient-derived organoids (PDOs) and tumor samples. They compared these with normal breast tissue data from The Cancer Genome Atlas Pan Cancer Atlas.
Their focus on amino acid metabolism paid off. They discovered that FAH, an enzyme in the tyrosine breakdown pathway, was enriched in breast tumors and linked to poorer survival rates in HR-positive breast cancer.
Surprisingly, FAH was found in high concentrations within the nuclei of breast cancer cells from patients who had relapsed on CDK4/6 inhibitors. Typically, FAH resides in the cellular cytoplasm, but it appears to relocate to the nucleus during CDK4/6 inhibition.
FAH’s Role in Resistance and a Potential Solution
Further experiments revealed that PDOs without FAH were more sensitive to CDK4/6 inhibition, while those with excess FAH were more resistant. However, this resistance wasn’t linked to FAH’s role in tyrosine breakdown.
Instead, the researchers observed that FAH interacts with CDK9, boosting CDK9 target genes. By disrupting this interaction with a CDK9 inhibitor, they were able to reverse the resistance caused by FAH.
This finding opens up new possibilities. Taru Muranen, PhD, a co-senior author, suggests that CDK9 inhibitors, currently in trials for other cancers, could be repurposed for advanced HR-positive breast cancer. She also highlights the potential for early intervention, combining CDK9 and CDK4/6 inhibitors for patients with FAH-positive tumor cells before treatment begins.
The study’s impact is twofold, according to Naama Kanarek, PhD, another co-senior author. It offers the potential for nuclear FAH to serve as a predictive biomarker and identifies patients who might benefit from CDK9 inhibition.
Potential for Early Intervention and Biomarker Use
FAH can be easily detected using standard immunohistochemistry, and with standardization of nuclear signals, it could serve as a biomarker for CDK4/6 inhibitor resistance. This would allow for more personalized treatment strategies, helping to overcome resistance and improve outcomes for HR-positive breast cancer patients.
Next Steps and Clinical Implications
The researchers plan to study nuclear FAH in a larger group of patient tumors to confirm its predictive value. They also emphasize the need for safety and efficacy studies of CDK9 inhibitors, noting that targeting the FAH-CDK9 interaction directly might be possible without affecting FAH’s metabolic function.
