Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

Logan Leak¹, Ziwei Wang², Alby J Joseph¹, Brianna Johnson¹, Alyssa A Chan¹, Cassandra M Decosto¹, Leslie Magtanong¹, Pin-Joe Ko¹, Weaverly Colleen Lee¹, Joan Ritho¹, Sophia Manukian¹, Alec Millner³, Shweta Chitkara³, Jennifer J Salinas⁴, Rachid Skouta^{5

6}, Matthew G Rees⁷, Melissa M Ronan⁷, Jennifer A Roth⁷, Chad L Myers⁸, Jason Moffat^{9

10}, Charles Boone^{10

11

12}, Steven J Bensinger^{13

14}, David A Nathanson^{4

15}, G Ekin Atilla-Gokcumen³, Everett J Moding², Scott J Dixon¹⁶

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. sjdixon@stanford.edu.

PMID: 40419770
DOI: 10.1038/s41589-025-01913-4

Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

Logan Leak et al. Nat Chem Biol. 2025 Dec.

. 2025 Dec;21(12):1873-1884.

doi: 10.1038/s41589-025-01913-4. Epub 2025 May 26.

Authors

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. sjdixon@stanford.edu.

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: D.A.N. is a founder of and holds equity in Katmai Pharmaceuticals and Trethera Corporation. E.J.M. has served as a paid consultant for Guidepoint and GLG. S.J.D. is an inventor on patents related to ferroptosis. The other authors declare no competing interests.

Update of

A clinical drug candidate that triggers non-apoptotic cancer cell death.
Dixon S, Leak L, Wang Z, Lee WC, Johnson B, Millner A, Ko PJ, Decosto C, Magtanong L, Ritho J, Skouta R, Atilla-Gokcumen E, Myers C, Moffat J, Boone C, Bensinger S, Moding E, Joseph A, Chan A, Chitkara S, Salinas J, Nathanson D. Dixon S, et al. Res Sq [Preprint]. 2025 Feb 11:rs.3.rs-4138879. doi: 10.21203/rs.3.rs-4138879/v1. Res Sq. 2025. Update in: Nat Chem Biol. 2025 Dec;21(12):1873-1884. doi: 10.1038/s41589-025-01913-4. PMID: 39989975 Free PMC article. Updated. Preprint.

References

1. Green, D. R. The coming decade of cell death research: five riddles. Cell 177, 1094–1107 (2019). - PubMed - PMC - DOI
1. Leak, L. & Dixon, S. J. Surveying the landscape of emerging and understudied cell death mechanisms. Biochim. Biophys. Acta Mol. Cell. Res. 1870, 119432 (2023). - PubMed - PMC - DOI
1. Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol. 33, 1282–1294 (2023).
1. Yuan, J. & Ofengeim, D. A guide to cell death pathways. Nat. Rev. Mol. Cell Biol. 25, 379–395 (2023).
1. Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017). - PubMed - PMC - DOI

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

Affiliations

Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical