Targeting METTL8 with Rabdosiin overcomes lenvatinib resistance in hepatocellular carcinoma
Yunpeng Liu1, Muhua Chen2, Xiang-Xu Wang1
1The Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, 710032, Xi'an, PR China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032, Xi'an, PR China.
Abstract:
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.
Insights
This study identifies METTL8 as a key driver of lenvatinib resistance in hepatocellular carcinoma (HCC). Targeting METTL8 with Rabdosiin can overcome resistance and restore sensitivity to lenvatinib treatment.
Area of Science:
- Hepatocellular Carcinoma Research
- Molecular Oncology
- Drug Resistance Mechanisms
Background:
- Lenvatinib is a vital first-line treatment for advanced hepatocellular carcinoma (HCC), improving survival for some patients.
- Resistance to lenvatinib poses a significant clinical challenge, limiting its long-term efficacy.
- Identifying molecular drivers of resistance is crucial for developing strategies to overcome treatment failure.
Purpose of the Study:
- To identify key molecular factors contributing to lenvatinib resistance in HCC.
- To explore therapeutic strategies for overcoming lenvatinib resistance.
- To evaluate METTL8 as a potential therapeutic target and biomarker for lenvatinib treatment.
Main Methods:
- Genome-wide CRISPR-Cas9 activation screen to identify resistance-associated genes.
- In vitro and in vivo assays to validate the role of METTL8.
- Immunohistochemical staining to correlate METTL8 expression with lenvatinib sensitivity in patient tissues.
- Natural compound library screening and virtual drug screening to identify METTL8 inhibitors.
Main Results:
- METTL8 was identified as a crucial gene mediating lenvatinib resistance in HCC.
- Elevated METTL8 expression was observed in lenvatinib-resistant HCC cells and correlated with decreased lenvatinib sensitivity in patient samples.
- Rabdosiin, a natural compound, was identified as a METTL8 inhibitor and demonstrated efficacy in overcoming METTL8-mediated lenvatinib resistance.
Conclusions:
- METTL8 is a novel therapeutic target for overcoming lenvatinib resistance in HCC.
- Targeting METTL8 can potentially restore lenvatinib sensitivity, enhancing treatment outcomes.
- METTL8 serves as a valuable biomarker for predicting lenvatinib response in HCC patients.
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