Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer.
Nature metabolism. 2025 Feb 06 [Epub ahead of print]
Jiao Li, Kaimeng Huang, Meha Thakur, Fiona McBride, Ananthan Sadagopan, Daniel S Gallant, Prateek Khanna, Yasmin Nabil Laimon, Bingchen Li, Razan Mohanna, Maolin Ge, Cary N Weiss, Mingkee Achom, Qingru Xu, Sayed Matar, Gwo-Shu Mary Lee, Kun Huang, Miao Gui, Chin-Lee Wu, Kristine M Cornejo, Toni K Choueiri, Birgitta A Ryback, Sabina Signoretti, Liron Bar-Peled, Srinivas R Viswanathan
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medicine, Harvard Medical School, Boston, MA, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA., Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China., Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medicine, Harvard Medical School, Boston, MA, USA. ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .