Cottone, Lucia;
Dunford, James;
Calcutt, Eleanor;
Gamble, Vicki;
Aksu, Filiz Senbabaoglu;
Ligammari, Lorena;
Wherry, Georgina;
... Cribbs, Adam P; + view all
(2025)
ATF4-mediated stress response as a therapeutic vulnerability in chordoma.
Molecular Oncology
10.1002/1878-0261.70176.
(In press).
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Abstract
Chordoma, a rare primary bone malignancy, currently lacks effective targeted therapies. Despite surgical resection and adjuvant radiotherapy, prognosis remains poor. Recent preclinical studies have highlighted potential therapeutic targets, including the transcription factor T-box transcription factor T (TBXT). However, clinical outcomes associated with therapies targeting TBXT remain underexplored or have been modest, warranting further investigation. In this study, we investigated the therapeutic potential of transfer RNA (tRNA) synthetase inhibitors in chordoma treatment. Focused compound screening identified distinct chemotypes targeting human glutamyl-prolyl-tRNA synthetase (EPRS) as being effective in reducing cell viability in chordoma cell lines through a cyclic AMP-dependent transcription factor (ATF4)-mediated stress response rather than through TBXT regulation. Mechanistically significant upregulation of ATF4 and associated stress response genes was identified with consecutive pro-apoptotic DNA damage-inducible transcript 3 protein (DDIT3)-mediated cell death. The prototypic EPRS inhibitor halofuginone demonstrated significant tumour growth inhibition in an in vivo patient-derived xenograft model. These results suggest that targeting metabolic stress pathways via ATF4 activation presents a novel therapeutic approach for chordoma, warranting further clinical investigation.
| Type: | Article |
|---|---|
| Title: | ATF4-mediated stress response as a therapeutic vulnerability in chordoma |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/1878-0261.70176 |
| Publisher version: | https://doi.org/10.1002/1878-0261.70176 |
| Language: | English |
| Additional information: | © 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | ATF4, chordoma, prolyl‐tRNA synthetase, stress response |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10218425 |
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