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

## TL;DR

This paper describes a drug candidate that causes cancer cell death through a new mechanism involving lipid metabolism.

## Contribution

The study identifies a novel non-apoptotic cell death pathway triggered by tegavivint in cancer cells.

## Key findings

- Tegavivint activates a unique non-apoptotic cell death mechanism in sarcomas and other cancers.
- The lipid metabolic enzyme TECR is essential for this cell death pathway.
- TECR promotes cell death via the synthesis of palmitate in response to the drug.

## 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.