Recently, Prof. Ming Kuang's research team from the First Affiliated Hospital, Sun Yat-sen University published a research paper entitled “METTL1-mediated m⁷G tRNA modification promotes lenvatinib resistance in hepatocellular carcinoma” online in Cancer Research, which deciphered novel mechanisms underlying lenvatinib resistance from a translation level perspective.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Over 70% of HCC are diagnosed at advanced stages, with very limited treatment options. The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced HCC. However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses.

Prof. Ming Kuang's research team has successfully constructed lenvatinib-resistant HCC cell lines and performed un-biased proteomic profiling. They found that METTL1 and WDR4, the two key components of the tRNA m⁷G methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. Moreover, HCC organoids with higher expressions of METTL1 and WDR4 tended to be more tolerant to lenvatinib and patients with low METTL1/WDR4 level had significantly better prognosis when receiving adjuvant lenvatinib treatment.

Functionally, knockdown of METTL1 overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m⁷G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, through TRAC sequencing, RNC seuencing and polysome qPCR, they further found that METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m⁷G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.

This work was supported by National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, GDSTC | Basic and Applied, Basic Research Foundation of Guangdong Province and China Postdoctoral Science Foundation.

Link to the article: 

https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-22-0963/709196/METTL1-mediated-m7G-tRNA-modification-promotes?redirectedFrom=fulltext