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<p>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.</p><p></p>

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Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

  • 期刊论文

  • 发表日期：

    2025年5月26日

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  • Logan Leak,
  • Ziwei Wang,
  • Alby J. Joseph,
  • Brianna Johnson,
  • Alyssa A. Chan,
  • Cassandra M. Decosto,
  • Leslie Magtanong,
  • Pin-Joe Ko,
  • Weaverly Colleen Lee,
  • Joan Ritho,
  • Sophia Manukian,
  • Alec Millner,
  • Shweta Chitkara,
  • Jennifer J. Salinas,
  • Rachid Skouta,
  • Matthew G. Rees,
  • Melissa M. Ronan,
  • Jennifer A. Roth,
  • Chad L. Myers,
  • Jason Moffat,
  • Charles Boone,
  • Steven J. Bensinger,
  • David A. Nathanson,
  • G. Ekin Atilla-Gokcumen,
  • Everett J. Moding,
  • Scott J. Dixon

摘要

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.