2. Academic Validation
  3. A clinical drug candidate that triggers non-apoptotic cancer cell death

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

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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