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Augmented Acyl-CoA Biosynthesis Promotes Resistance to TEAD Palmitoylation Site Inhibition.
Kayla Nutsch1, Marissa N Trujillo2, Lirui Song3
1Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037-1000, United States.
ACS Chemical Biology
|April 3, 2025
Summary
Cancer cells become resistant to TEAD inhibitors when coenzyme A biosynthesis is enhanced. Increased palmitoyl-CoA levels outcompete drugs, revealing a new resistance mechanism against YAP-TEAD targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The YAP-TEAD transcriptional complex promotes cancer growth and resistance to targeted therapies.
- TEAD inhibitors are emerging therapeutics, but their resistance mechanisms are poorly understood.
Purpose of the Study:
- To investigate potential resistance mechanisms against TEAD inhibitors.
- To explore the role of coenzyme A biosynthesis in YAP-dependent cancer cell response to TEAD inhibition.
Main Methods:
- Genetic augmentation of de novo coenzyme A biosynthesis in YAP-dependent cancer cells.
- Assessment of cancer cell sensitivity to TEAD inhibitors.
- Analysis of palmitoyl-CoA levels and drug-target engagement.
Main Results:
- Enhanced de novo coenzyme A biosynthesis desensitizes YAP-dependent cancer cells to TEAD inhibitors.
- Increased palmitoyl-CoA levels were observed, which compete with TEAD inhibitors for binding.
- This suggests a novel resistance mechanism involving lipid metabolism.
Conclusions:
- Augmenting coenzyme A biosynthesis confers resistance to TEAD inhibitors by increasing palmitoyl-CoA.
- This finding uncovers a resistance mechanism to TEAD palmitoylation site inhibition.
- Implications for developing future combinatorial treatments in clinical settings.
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