School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Abstract: Sorafenib, a multi-target tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC), provides only modest survival benefits due to acquired resistance. The novel platinum-based drug, Pt1a, has demonstrated anti-cancer properties by degrading the epithelial-mesenchymal transition marker vimentin, a known mediator of sorafenib resistance. Therefore, we investigated whether Pt1a can sensitize HCC cells to sorafenib. In cultured HCC cells and patient-derived organoids, the combination of sorafenib and Pt1a synergistically reduced cell viability, attenuated self-renewal, and promoted cell apoptosis compared to single-drug treatment. In contrast, this synergistic effect was not observed in the immortalized human hepatocyte cell line MIHA. These findings were further validated in HCC patient-derived xenograft and NRAS/AKT-driven HCC mouse models. Notably, in the NRAS/AKT-driven HCC mouse model, the combination of sorafenib and Pt1a demonstrated superior efficacy compared to anti-VEGFA combined with anti-PD-L1 antibody treatment, which is the current first-line treatment for HCC. Mechanistically, RNA-sequencing and thermal proteome profiling revealed enrichment of m6A-related pathways under combination treatment, with an elevated m6A level confirmed by m6A dot blotting. The m6A writer METTL14 was identified as a potential mediator of the synergistic effect through functional CRISPR-knockout experiments. GLORI-sequencing was performed to identify the downstream m6A target genes of METTL14, and a combined signature of these genes predicted better survival in HCC patients and a negative correlation with cancer stemness. Our findings suggested Pt1a could synergize with sorafenib to inhibit HCC through METTL14-mediated m6A modification. This research provides valuable insights into the potential of Pt1a to overcome sorafenib resistance and opens avenues for novel treatment strategies for HCC.
