A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer
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.
Authors
- Boryana Petrova (ORCID: https://orcid.org/0000-0001-9996-9353)
- Jenny M. Hogstrom (ORCID: https://orcid.org/0000-0001-5932-0146)
- Hanna M. Doh (ORCID: https://orcid.org/0000-0003-0781-611X)
- Gerburg M. Wulf (ORCID: https://orcid.org/0000-0001-7868-6231)
- Laura C. Collins (ORCID: https://orcid.org/0000-0001-6751-4792)
- Jonathan L. Coloff (ORCID: https://orcid.org/0000-0003-4726-3097)
- Naama Kanarek (ORCID: https://orcid.org/0000-0002-2068-3908)
- Taru E. Muranen (ORCID: https://orcid.org/0000-0003-4158-9002)
- Camila Perea
- Kayla A. Cruz (ORCID: https://orcid.org/0000-0001-8880-5804)
- Jonathan D. Lee (ORCID: https://orcid.org/0000-0002-1229-0098)
- Michal Weitman
- Conor L. Evans (ORCID: https://orcid.org/0000-0003-2185-6505)
- Nina V. Kozlova (ORCID: https://orcid.org/0000-0002-4944-7917)
- Peng Wang (ORCID: https://orcid.org/0000-0001-8118-4929)
- Aidan Kump
- Jaymin M. Patel (ORCID: https://orcid.org/0000-0001-9945-5555)
- Su Min Hong (ORCID: https://orcid.org/0009-0006-8472-9924)
- Arjun Garg (ORCID: https://orcid.org/0009-0003-1676-630X)
- Kaisa Koivula
Institutions
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Cornell University (US)
- University of Illinois Chicago (US)
- Massachusetts General Hospital (US)
- Presbyterian Hospital (US)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1126/sciadv.aef1145
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00