Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma

Jiao Li^{1

2}, Kaimeng Huang^{2

3}, Meha Thakur¹, Fiona McBride¹, Ananthan Sadagopan¹, Daniel S Gallant¹, Prateek Khanna¹, Yasmin Nabil Laimon⁴, Bingchen Li^{1

2}, Razan Mohanna⁴, Maolin Ge⁵, Cary N Weiss^{1

6}, Mingkee Achom^{1

2}, Qingru Xu¹, Sayed Matar⁴, Gwo-Shu Mary Lee¹, Kun Huang⁷, Miao Gui⁸, Chin-Lee Wu⁹, Kristine M Cornejo⁹, Toni K Choueiri^{1

2

10}, Birgitta A Ryback¹¹, Sabina Signoretti⁴, Liron Bar-Peled^{12

13}, Srinivas R Viswanathan^{14

15

16}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
⁹ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Department of Medicine, Harvard Medical School, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹³ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. srinivas.viswanathan@dfci.harvard.edu.
¹⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA. srinivas.viswanathan@dfci.harvard.edu.
¹⁶ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. srinivas.viswanathan@dfci.harvard.edu.

PMID: 39915638
DOI: 10.1038/s42255-025-01218-9

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma

Jiao Li et al. Nat Metab. 2025 Mar.

. 2025 Mar;7(3):478-492.

doi: 10.1038/s42255-025-01218-9. Epub 2025 Feb 6.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
⁹ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Department of Medicine, Harvard Medical School, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹³ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. lbar-peled@mgh.harvard.edu.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. srinivas.viswanathan@dfci.harvard.edu.
¹⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA. srinivas.viswanathan@dfci.harvard.edu.
¹⁶ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. srinivas.viswanathan@dfci.harvard.edu.

PMID: 39915638
DOI: 10.1038/s42255-025-01218-9

Abstract

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.

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Conflict of interest statement

Competing interests: S.R.V. has consulted for Jnana Therapeutics within the past 3 years and receives research support from Bayer. L.B.-P. is a co-founder, holds equity in and is a consultant for Scorpion Therapeutics. T.K.C. reports institutional and/or personal paid and/or unpaid support for research, advisory board, consultancy, and/or honoraria past 5 years from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Bicycle Therapeutics, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GSK, Gilead, HiberCell, IQVA, Infinity, Institut Servier, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME and non-CME events (Mashup Media Peerview, OncLive, MJH, CCO and others), outside the submitted work; institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA; equity from Tempest, Pionyr, Osel, PrecedeBio, CureResponse, InnDura Therapeutics, and Primium, Abalytics; is a committee member for NCCN, the GU Steering Committee, ASCO, ESMO, ACCRU, and KidneyCan; medical writing and editorial assistance support that might have been founded by communications companies in part, no speaker’s bureau; mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. S.S. reports receiving commercial research grants from Bristol Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck & Co., Rahway, NJ, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics AG, AACR and NCI; and receives royalties from Biogenex. The other authors declare no competing interests.

Update of

TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma.
Li J, Huang K, McBride F, Sadagopan A, Gallant DS, Thakur M, Khanna P, Li B, Ge M, Weiss CN, Achom M, Xu Q, Huang K, Ryback BA, Gui M, Bar-Peled L, Viswanathan SR. Li J, et al. bioRxiv [Preprint]. 2024 Aug 10:2024.08.09.607311. doi: 10.1101/2024.08.09.607311. bioRxiv. 2024. Update in: Nat Metab. 2025 Mar;7(3):478-492. doi: 10.1038/s42255-025-01218-9. PMID: 39149323 Free PMC article. Updated. Preprint.

References

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Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma

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Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma

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