FASN Inhibition Resensitizes Chordoma to Radiotherapy by Targeting Adaptive Unsaturated Fatty Acid Metabolism

Area of Science:

• Oncology
• Metabolic Research
• Cancer Biology

Background:

• Chordoma, a rare skull base and spine tumor, is resistant to conventional therapies like chemotherapy and radiotherapy, often leading to recurrence.
• Recurrent chordoma demonstrates a metabolic shift involving monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs), contributing to its aggressive nature.

Purpose of the Study:

• To investigate the role of fatty acid metabolism in chordoma radioresistance.
• To identify potential therapeutic targets for overcoming treatment resistance in chordoma.

Main Methods:

• Single-cell metabolic profiling to analyze tumor subpopulations.
• Mechanistic studies involving reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, SREBP1, and Fatty Acid Synthase (FASN).
• In silico and pharmacologic inhibition of FASN in vitro and in vivo models.

Main Results:

• Chordoma recurrence correlates with increased MUFAs and PUFAs, a low PUFA/MUFA ratio, and resistance to lipid peroxidation.
• Elevated FASN and lipid droplet accumulation confer radioresistance, with MUFA loading mimicking this effect.
• Inhibition of FASN restored radiosensitivity and induced apoptosis in chordoma models.

Conclusions:

• Adaptive fatty acid metabolism, particularly FASN activity, is a key mechanism of radioresistance in chordoma.
• Targeting FASN represents a promising strategy for radiosensitization in chordoma, especially when radiotherapy dose escalation is limited.