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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
PubMed

Insights

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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