Abstract:
Background:
BRAF-targeted therapy has provided an important therapeutic option for patients with BRAFV600E-mutant thyroid cancer; however, adaptive resistance limits its therapeutic efficacy. The metabolic mechanisms underlying adaptive resistance to BRAF inhibition remain incompletely understood. Here, we investigated the role of fatty acid oxidation (FAO) and its metabolic-epigenetic consequences in thyroid cancer cells exposed to BRAF inhibition.
Methods:
Integrated transcriptomic and metabolomic analyses were performed to characterize metabolic alterations induced by BRAF inhibition. The functional role of FAO was evaluated using pharmacological inhibition and complementary in vitro and in vivo models. Intracellular acetyl-CoA levels and histone H3 lysine 9 acetylation (H3K9ac) were examined to investigate the connection between metabolic remodeling and epigenetic regulation. The downstream role of RUNX1 was further evaluated using molecular and functional assays. The therapeutic relevance of FAO inhibition combined with BRAF inhibition was assessed in tumor models and a patient-derived organoid model.
Results:
BRAF inhibition with vemurafenib significantly enhanced FAO in thyroid cancer cells. This metabolic adaptation was associated with increased PGC1α expression and elevated intracellular acetyl-CoA. Pharmacological inhibition of FAO with thioridazine enhanced the antitumor activity of BRAF inhibition and suppressed tumor growth in vitro and in vivo, with consistent effects observed in a patient-derived organoid model. Mechanistically, increased FAO-derived acetyl-CoA altered the H3K9ac landscape and promoted epigenetic activation of pro-survival genes, including RUNX1. RUNX1 expression was associated with poorer prognosis in thyroid cancer, while functional depletion of RUNX1 reduced thyroid cancer cell proliferation, migration, and invasion.
Conclusion:
Our findings identify a FAO–acetyl-CoA–H3K9ac metabolic-epigenetic axis that contributes to adaptive resistance to BRAF inhibition in BRAFV600E-mutant thyroid cancer. Targeting FAO may provide a potential strategy to enhance the therapeutic efficacy of BRAF-targeted therapy.
