A clinical drug candidate that triggers non-apoptotic cancer cell death

  • Res Sq. 2025 Feb 11:rs.3.rs-4138879. doi: 10.21203/rs.3.rs-4138879/v1.
Scott Dixon  1 ,  Logan Leak  1 ,  Ziwei Wang  2 ,  Weaverly Colleen Lee  1 ,  Brianna Johnson  1 ,  Alec Millner  3 ,  Pin-Joe Ko  1 ,  Cassandra Decosto  1 ,  Leslie Magtanong  1 ,  Joan Ritho  1 ,  Rachid Skouta  4 ,  Ekin Atilla-Gokcumen  3 ,  Chad Myers  5 ,  Jason Moffat ,  Charles Boone  6 ,  Steven Bensinger  7 ,  Everett Moding  1 ,  Alby Joseph  1 ,  Alyssa Chan  1 ,  Shweta Chitkara  8 ,  Jenny Salinas  9 ,  David Nathanson  9
Affiliations
  • 1. Stanford University.
  • 2. Stanford University School of Medicine.
  • 3. University at Buffalo, SUNY.
  • 4. University of Massachusetts.
  • 5. University of Minnesota-Twin Cities.
  • 6. University of Toronto.
  • 7. University of California Los Angeles.
  • 8. University at Buffalo.
  • 9. University of Ccalifornia Los Angeles.
PMID: 39989975 DOI: 10.21203/rs.3.rs-4138879/v1
Abstract

Small molecules that induce non-apoptotic 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 non-apoptotic 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 non-apoptotic 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 non-apoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.

Keywords
TECR; cancer; necrosis; palmitate.
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