Inhibition of ACSS2 enhances cabozantinib sensitivity by blocking TFEB-induced autophagic flux in hepatocellular carcinoma
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins et d'échantillons hépatiques issus de patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel l'inhibition de l'acétyl-CoA synthétase 2 augmente la sensibilité des cellules cancéreuses au cabozantinib en bloquant l'autophagie protectrice induite par le facteur de transcription EB
Background : Cabozantinib, a promising tyrosine kinase inhibitor (TKI), has recently been approved by the Food and Drug Administration (FDA) to treat hepatocellular carcinoma (HCC). However, the objective response rate (ORR) of cabozantinib as monotherapy is low. Therefore, there is an urgent need to develop cabozantinib-based combination therapy.
Methods : RNA-sequencing was used to analyse the gene expression alterations in HCC cells after cabozantinib treatment. A luciferase reporter assay was used to measure TFEB transcriptional activity. In vitro and in vivo studies were applied to assess the effect of cabozantinib in combination with autophagy inhibitors on HCC.
Results : Our results showed that cabozantinib induces autophagic flux, which protects HCC cells from cabozantinib-induced growth inhibition and apoptosis. Further mechanistic studies showed that cabozantinib upregulates Acetyl-CoA Synthetase 2 (ACSS2) and promotes its nuclear translocation, which subsequently activates transcription factor EB (TFEB). TFEB then binds to lysosomal and autophagy gene promoter regions, thereby promoting lysosomal biogenesis and inducing autophagy. In addition, the combination use of an ACSS2 inhibitor or chloroquine (CQ) enhances the antitumor efficacy of cabozantinib in HCC both in vitro and in vivo.
Conclusion : Our study proposes a novel molecular mechanism of cabozantinib and provides insights into cabozantinib-based combination therapy for HCC.
British Journal of Cancer , article en libre accès, 2026