Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

  • Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01913-4.
Logan Leak  1 ,  Ziwei Wang  2 ,  Alby J Joseph  1 ,  Brianna Johnson  1 ,  Alyssa A Chan  1 ,  Cassandra M Decosto  1 ,  Leslie Magtanong  1 ,  Pin-Joe Ko  1 ,  Weaverly Colleen Lee  1 ,  Joan Ritho  1 ,  Sophia Manukian  1 ,  Alec Millner  3 ,  Shweta Chitkara  3 ,  Jennifer J Salinas  4 ,  Rachid Skouta  5  6 ,  Matthew G Rees  7 ,  Melissa M Ronan  7 ,  Jennifer A Roth  7 ,  Chad L Myers  8 ,  Jason Moffat  9  10 ,  Charles Boone  10  11  12 ,  Steven J Bensinger  13  14 ,  David A Nathanson  4  15 ,  G Ekin Atilla-Gokcumen  3 ,  Everett J Moding  2 ,  Scott J Dixon  16
Affiliations
  • 1. Department of Biology, Stanford University, Stanford, CA, USA.
  • 2. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA.
  • 4. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 5. Department of Chemistry, University of Massachusetts, Amherst, Amherst, MA, USA.
  • 6. Department of Biology, University of Massachusetts, Amherst, Amherst, MA, USA.
  • 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 8. Department of Computer Science and Engineering, Bioinformatics and Computational Biology Graduate Program, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
  • 9. Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 10. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 11. Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • 12. RIKEN Center for Sustainable Resource Science, Saitama, Japan.
  • 13. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 14. UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA, USA.
  • 15. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 16. Department of Biology, Stanford University, Stanford, CA, USA. [email protected].
PMID: 40419770 DOI: 10.1038/s41589-025-01913-4
Abstract

Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other Cancer cells. This lethal mechanism is distinct from Ferroptosis, Necroptosis and Pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain Fatty Acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.

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