Inhibition of ACSS2 enhances cabozantinib sensitivity by blocking TFEB-induced autophagic flux in hepatocellular carcinoma.

backgroundCabozantinib, 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.

methodsRNA-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.

resultsOur 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.

conclusionOur study proposes a novel molecular mechanism of cabozantinib and provides insights into cabozantinib-based combination therapy for HCC.