Integrin subunit beta 8 contributes to lenvatinib resistance in liver cancer

Abstract

Lenvatinib is a multi‐kinase inhibitor approved as a first‐line therapy for advanced hepatocellular carcinoma (HCC), a major type of liver cancer. However, the development of drug resistance is common, and the underlying mechanisms are largely unknown. In this study, we established two lenvatinib‐resistant (LR) HCC cell lines and identified integrin subunit beta 8 (ITGB8) as a critical contributor to lenvatinib resistance in HCC. The elevated expression of ITGB8 was observed in LR HCC cells. Furthermore, silencing of ITGB8 reversed lenvatinib resistance in vitro and in vivo, whereas ectopic expression of ITGB8 in lenvatinib‐sensitive parental HCC cells exhibited increased resistance to lenvatinib. Mechanistically, ITGB8 regulated lenvatinib resistance through an AKT‐dependent signaling pathway, in which HSP90 was involved. In supporting this model, either an AKT inhibitor MK‐2206 or an HSP90 inhibitor 17‐AAG re‐sensitized LR HCC cells to lenvatinib treatment. Collectively, our results establish a crucial role and novel mechanism of ITGB8 in lenvatinib resistance, and suggest that targeting the ITGB8/HSP90/AKT axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance.