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Autophagy sustains mitochondrial respiration and determines resistance to BRAFV600E inhibition in thyroid carcinoma

Sergio Díaz-Gago1, Javier Vicente-Gutiérrez1, Jose Manuel Ruiz-Rodríguez1

  • 1Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Biología de Sistemas, Unidad de Bioquímica y Biología Molecular, Madrid, Spain.

Autophagy
|March 4, 2024
PubMed

Insights

Thyroid cancer cells rely on fatty acid oxidation for survival, regulated by autophagy. Inhibiting autophagy forces cells to use glycolysis, increasing sensitivity to vemurafenib, a BRAF inhibitor.

Area of Science:

  • Metabolic pathways in cancer
  • Molecular mechanisms of thyroid cancer
  • Autophagy and cancer therapeutics

Background:

  • BRAFV600E mutation is common in thyroid cancer, linked to poor outcomes and resistance to targeted therapies.
  • Advanced thyroid tumors like anaplastic thyroid carcinomas respond poorly to current BRAFV600E inhibitors.
  • Understanding alternative survival mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the metabolic dependencies of thyroid tumor cells for potential therapeutic exploitation.
  • To explore the role of autophagy in regulating fatty acid oxidation and cellular respiration.
  • To assess the impact of modulating autophagy and glycolysis on sensitivity to BRAFV600E inhibitors.

Main Methods:

  • Analysis of thyroid carcinoma cell respiration and its dependence on fatty acid oxidation (FAO).
  • Investigation of macroautophagy/autophagy's role in regulating mitochondrial fatty acid availability.
  • Assessment of cell survival and drug sensitivity following inhibition of autophagy, FAO, or glycolysis.

Main Results:

  • Thyroid carcinoma cell respiration is highly dependent on FAO, with mitochondrial fatty acid availability regulated by autophagy.
  • Inhibition of autophagy or lysosomal function enhances lipolysis, but this is not essential for cell survival.
  • Thyroid tumor cells compensate for impaired oxidative phosphorylation by increasing glycolysis; this glycolytic boost is essential for survival in autophagy-deficient cells and enhances sensitivity to vemurafenib.

Conclusions:

  • Autophagy plays a key role in thyroid cancer metabolism by regulating FAO.
  • Targeting glycolysis in combination with BRAFV600E inhibition offers a promising therapeutic strategy.
  • Mitochondrial targeting combined with vemurafenib may be effective for eliminating BRAFV600E-positive thyroid carcinoma cells.
Keywords:
Cancer metabolismfatty acid oxidationglycolysisoxidative phosphorylationthyroid cancervemurafenib resistance

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