Identification and Therapeutic Targeting of METTL8-Mediated Lenvatinib Resistance in Hepatocellular Carcinoma Using Rabdosiin.

Exp Cell Res

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, Air Force Medical University, 710032 Xi'an, PR China. Electronic address:

Published: December 2024

In hepatocellular carcinoma (HCC), lenvatinib is a key first-line treatment that significantly improves survival in some patients with advanced stage. However, lenvatinib resistance presents a major clinical challenge. This study aims to identify key molecular factors driving lenvatinib resistance in HCC and propose intervention strategies to overcome this resistance, thereby enhancing therapeutic efficacy. A genome-wide CRISPR-Cas9 activation screen identified METTL8 as a crucial gene associated with lenvatinib resistance. Validation through in vitro and in vivo assays confirmed METTL8's role in mediating lenvatinib resistance. Higher METTL8 expression was observed in lenvatinib-resistant HCC cells compared to parental cells. Immunohistochemical staining of tissue sections from HCC patients revealed a negative correlation between high METTL8 expression and lenvatinib sensitivity. To inhibit the function of METTL8 that mediate lenvatinib resistance, we conducted a screening using a natural compound library, virtual drug screening identified Rabdosiin as a potential METTL8 inhibitor, subsequent experiments demonstrated that Rabdosiin could effectively overcome METTL8-mediated lenvatinib resistance. In conclusion, this research highlights METTL8 as a novel target for mitigating lenvatinib resistance, proposing that targeting METTL8 could restore lenvatinib sensitivity in HCC, and underscores its value as a biomarker for lenvatinib application in clinical settings.

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http://dx.doi.org/10.1016/j.yexcr.2024.114389DOI Listing

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  • - Lenvatinib is a key treatment for hepatocellular carcinoma (HCC) that works by blocking critical growth factor receptors, which helps reduce tumor growth and improves immune response.
  • - Although lenvatinib is effective on its own, drug resistance is a growing issue due to factors like genetic mutations and changes in the tumor environment.
  • - Combining lenvatinib with immune checkpoint inhibitors could enhance treatment effectiveness, but challenges related to safety remain, highlighting the need for research on resistance mechanisms and biomarkers for better personalized therapies.
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Identification and Therapeutic Targeting of METTL8-Mediated Lenvatinib Resistance in Hepatocellular Carcinoma Using Rabdosiin.

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December 2024

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, Air Force Medical University, 710032 Xi'an, PR China. Electronic address:

In hepatocellular carcinoma (HCC), lenvatinib is a key first-line treatment that significantly improves survival in some patients with advanced stage. However, lenvatinib resistance presents a major clinical challenge. This study aims to identify key molecular factors driving lenvatinib resistance in HCC and propose intervention strategies to overcome this resistance, thereby enhancing therapeutic efficacy.

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