ATF4-mediated stress response as a therapeutic vulnerability in chordoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Chordoma is a rare bone cancer with poor prognosis and limited targeted therapies.
• Existing treatments like surgery and radiotherapy have suboptimal outcomes.
• Transcription factor T-box transcription factor T (TBXT) has shown potential but requires further investigation.

Purpose of the Study:

• To investigate the therapeutic potential of transfer RNA (tRNA) synthetase inhibitors for chordoma.
• To explore the underlying molecular mechanisms of these inhibitors in chordoma cells.
• To evaluate the efficacy of a specific inhibitor in a preclinical chordoma model.

Main Methods:

• Focused compound screening of tRNA synthetase inhibitors.
• Assessment of cell viability and gene expression in chordoma cell lines.
• Analysis of the cyclic AMP-dependent transcription factor 4 (ATF4) pathway and stress response genes.
• In vivo efficacy study using a patient-derived xenograft model.

Main Results:

• Distinct chemotypes targeting human glutamyl-prolyl-tRNA synthetase (EPRS) reduced chordoma cell viability.
• Inhibitor efficacy was mediated by ATF4 activation and subsequent stress response, not TBXT.
• Upregulation of ATF4 led to DNA damage-inducible transcript 3 protein (DDIT3)-mediated apoptosis.
• Halofuginone, a prototypic EPRS inhibitor, significantly inhibited tumor growth in vivo.

Conclusions:

• Targeting metabolic stress pathways through ATF4 activation is a novel therapeutic strategy for chordoma.
• EPRS inhibitors represent a promising class of drugs for chordoma treatment.
• Further clinical investigation of ATF4-mediated therapies is warranted for chordoma patients.