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Integrin subunit beta 8 contributes to lenvatinib resistance in HCC

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‐resista...

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Autores principales: Hou, Wei, Bridgeman, Bryan, Malnassy, Greg, Ding, Xianzhong, Cotler, Scott J., Dhanarajan, Asha, Qiu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234648/
https://www.ncbi.nlm.nih.gov/pubmed/35238496
http://dx.doi.org/10.1002/hep4.1928
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author Hou, Wei
Bridgeman, Bryan
Malnassy, Greg
Ding, Xianzhong
Cotler, Scott J.
Dhanarajan, Asha
Qiu, Wei
author_facet Hou, Wei
Bridgeman, Bryan
Malnassy, Greg
Ding, Xianzhong
Cotler, Scott J.
Dhanarajan, Asha
Qiu, Wei
author_sort Hou, Wei
collection PubMed
description 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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spelling pubmed-92346482022-06-30 Integrin subunit beta 8 contributes to lenvatinib resistance in HCC Hou, Wei Bridgeman, Bryan Malnassy, Greg Ding, Xianzhong Cotler, Scott J. Dhanarajan, Asha Qiu, Wei Hepatol Commun Original Articles 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. John Wiley and Sons Inc. 2022-03-03 /pmc/articles/PMC9234648/ /pubmed/35238496 http://dx.doi.org/10.1002/hep4.1928 Text en © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Hou, Wei
Bridgeman, Bryan
Malnassy, Greg
Ding, Xianzhong
Cotler, Scott J.
Dhanarajan, Asha
Qiu, Wei
Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title_full Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title_fullStr Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title_full_unstemmed Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title_short Integrin subunit beta 8 contributes to lenvatinib resistance in HCC
title_sort integrin subunit beta 8 contributes to lenvatinib resistance in hcc
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234648/
https://www.ncbi.nlm.nih.gov/pubmed/35238496
http://dx.doi.org/10.1002/hep4.1928
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