A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer
6 affiliations
- 1Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- 2Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
- 3Core Facilities, Medical University of Vienna, Vienna, Austria.
- 4Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- 5Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA.
- 6Department of Pathology, and Laboratory Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA.
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.
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BibTeX
@article{hogstrom2026noncanonical,
title = {{A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer}},
author = {Jenny Högström and Hanna M. Doh and Aidan Kump and Boryana Petrova and Peng Wang and Jonathan D. Lee and Kaisa Koivula and Nina Kozlova and Kayla A. Cruz and Su Min Hong and Camila Perea and Arjun Garg and Michal Weitman and Conor L. Evans and Jonathan L. Coloff and Jaymin M. Patel and Gerburg M. Wulf and Laura C. Collins and Naama Kanarek and Taru Muranen},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aef1145},
url = {https://www.science.org/doi/10.1126/sciadv.aef1145},
note = {CC BY},
}
RIS
TY - JOUR
TI - A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer
AU - Jenny Högström
AU - Hanna M. Doh
AU - Aidan Kump
AU - Boryana Petrova
AU - Peng Wang
AU - Jonathan D. Lee
AU - Kaisa Koivula
AU - Nina Kozlova
AU - Kayla A. Cruz
AU - Su Min Hong
AU - Camila Perea
AU - Arjun Garg
AU - Michal Weitman
AU - Conor L. Evans
AU - Jonathan L. Coloff
AU - Jaymin M. Patel
AU - Gerburg M. Wulf
AU - Laura C. Collins
AU - Naama Kanarek
AU - Taru Muranen
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aef1145
UR - https://www.science.org/doi/10.1126/sciadv.aef1145
AB - 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.
SN - 2375-2548
ER -