p53-R280S mutation confers lenvatinib resistance in hepatocellular carcinoma via Bcl-2-mediated anti-apoptotic signaling

Lenvatinib is approved as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), however, its clinical efficacy is frequently limited by the emergence of drug resistance. This study aimed to elucidate the underlying mechanisms by which HCC develops resistance to lenvatinib. Lenvatinib-resistant HCC cell lines were established and subjected to RNA sequencing (RNA-seq) to identify genes associated with drug resistance. HCC cell lines stably overexpressing the p53 R280S mutation were constructed via lentiviral transduction. The effects of p53 R280S on HCC cell proliferation, apoptotic, and lenvatinib sensitivity were evaluated using Cell Counting Kit-8 (CCK-8) assays, flow cytometry, colony formation assays, TUNEL staining, and a mouse subcutaneous xenograft model. The underlying molecular mechanisms were further investigated by Western blotting, immunohistochemical staining (IHC), and quantitative real-time PCR (qRT-PCR). RNA sequencing of lenvatinib-resistant HCC cell lines revealed p53 dysregulation, and sanger sequencing identified the p53 R280S missense mutation, which was shown to enhance lenvatinib resistance in vitro and in vivo. The p53 R280S mutant attenuated lenvatinib-induced apoptosis. Furthermore, mutant p53 upregulated Bcl-2 expression and downregulated BAX expression, thereby suppressing apoptotic signaling. The p53 R280S mutation promotes lenvatinib resistance in HCC by inhibiting apoptosis.