Abstract 3066: Fumarylacetoacetate hydrolase (FAH) stimulates resistance to CDK4/6 inhibitors in hormone receptor-positive breast cancer via a novel non-canonical function

Abstract Breast cancer is the most prevalent cancer among women worldwide with hormone receptor-positive (HR+) cancer constituting 70% of all breast cancers. HR+ breast cancer patients are usually treated with targeted therapies, which include hormone therapy, as well as CDK4/6- and PI3K-inhibitors. Unfortunately, the tumors usually become resistant over time. In addition to genetic drivers of resistance, metabolic perturbations and enhanced activity of metabolic enzymes can also contribute to tumor growth, resistance and poor survival. We have discovered that Fumarylacetoacetate hydrolase (FAH), the last enzyme in tyrosine catabolism pathway, is enriched in HR+ breast tumors and correlates with poor survival. By using HR+ patient-derived organoid cultures (PDOs), we show that FAH stimulates resistance to multiple standard-of-care therapies. Despite its canonical function in tyrosine catabolism, FAH overexpressing cells do not preferentially utilize the tyrosine catabolism pathway. Instead, we surprisingly observe increased nuclear localization of FAH in patients treated with endocrine therapy and/or CDK4/6-inhibitors. Similarly, ER degraders and CDK4/6-inhibitors increase the ratio of nuclear FAH in patient-derived organoids, suggesting that the nuclear localization could drive resistance. To investigate this, we cloned a nuclear localization signal (NLS) to FAH and observed that FAH-NLS expressing PDOs were more resistant to CDK4/6-inhibitors. In contrast, blocking the nuclear translocation reversed the FAH-mediated resistance, showing that the nuclear localization is essential for the resistance phenotype. Collectively this suggests a yet uncharacterized moonlighting function of FAH in the nucleus and links this metabolic enzyme to treatment resistance in HR+ breast cancer. Citation Format: Jenny Hogstrom, Boryana Petrova, Hanna Doh, Camila Perea, Su Min Hong, Nina Kozlova, Kayla Cruz, Conor L. Evans, Jonah Lee, John Clohessy, Gerburg Wulf, Laura Collins, Naama Kanarek, Taru Muranen. Fumarylacetoacetate hydrolase (FAH) stimulates resistance to CDK4/6 inhibitors in hormone receptor-positive breast cancer via a novel non-canonical function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3066.