Integrin subunit beta 8 contributes to lenvatinib resistance in HCC.
Wei Hou1,2, Bryan Bridgeman1,2, Greg Malnassy1,2
1Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
Hepatology Communications
|March 3, 2022
Summary
Integrin subunit beta 8 (ITGB8) drives lenvatinib resistance in liver cancer. Targeting the ITGB8/HSP90/AKT pathway can overcome this resistance, offering a new therapeutic strategy for hepatocellular carcinoma (HCC) patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance Mechanisms
Background:
- Lenvatinib is a key treatment for advanced hepatocellular carcinoma (HCC).
- Drug resistance frequently limits lenvatinib efficacy in HCC.
- Mechanisms underlying lenvatinib resistance remain largely undefined.
Purpose of the Study:
- To identify novel molecular drivers of lenvatinib resistance in HCC.
- To elucidate the functional role of identified targets in mediating resistance.
- To explore potential therapeutic strategies to overcome lenvatinib resistance.
Main Methods:
- Established two lenvatinib-resistant (LR) HCC cell lines.
- Assessed the expression and function of integrin subunit beta 8 (ITGB8) in LR and sensitive HCC cells.
- Investigated the role of ITGB8 in lenvatinib resistance in vitro and in vivo.
- Explored the downstream signaling pathways involving HSP90 and AKT.
- Evaluated the efficacy of targeting the ITGB8/HSP90/AKT axis with specific inhibitors.
Main Results:
- Elevated ITGB8 expression was identified in LR HCC cells.
- Silencing ITGB8 reversed lenvatinib resistance, while its ectopic expression conferred resistance.
- ITGB8 mediated resistance via HSP90-dependent stabilization of AKT and enhanced AKT signaling.
- AKT inhibitor MK-2206 and HSP90 inhibitor 17-AAG resensitized LR HCC cells to lenvatinib.
Conclusions:
- ITGB8 is a critical mediator of lenvatinib resistance in HCC.
- The ITGB8/HSP90/AKT signaling axis plays a pivotal role in this resistance.
- Targeting the ITGB8/HSP90/AKT pathway represents a promising therapeutic approach for lenvatinib-resistant HCC.
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