1. Academic Validation
  2. Integrin subunit beta 8 contributes to lenvatinib resistance in HCC

Integrin subunit beta 8 contributes to lenvatinib resistance in HCC

  • Hepatol Commun. 2022 Jul;6(7):1786-1802. doi: 10.1002/hep4.1928.
Wei Hou 1 2 Bryan Bridgeman 1 2 Greg Malnassy 1 2 Xianzhong Ding 3 Scott J Cotler 4 Asha Dhanarajan 4 Wei Qiu 1 2
Affiliations

Affiliations

  • 1 Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
  • 2 Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
  • 3 Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
  • 4 Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
Abstract

Lenvatinib is a multikinase inhibitor approved as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the underlying mechanisms governing this resistance 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 HSP90-mediated stabilization of Akt and enhanced Akt signaling. In support of this model, either an Akt Inhibitor MK-2206 or an HSP90 Inhibitor 17-AAG resensitized LR HCC cells to lenvatinib treatment. Conclusion: Collectively, our results establish a crucial role of ITGB8 in lenvatinib resistance, and suggest that targeting the ITGB8/HSP90/Akt axis is a promising therapeutic strategy in patients with HCC exhibiting lenvatinib resistance.

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