METTL13 enzyme found to fuel cancer growth by boosting KRAS protein production

A study published in Nature Cell Biology on October 29, 2026, led by MD Anderson Cancer Center and St. Jude Children's Research Hospital, revealed that the enzyme METTL13 drives KRAS protein overproduction and drug resistance in cancer cells. METTL13 methylates the eEF1A protein at lysine 55, accelerating translation of wobble-codon-rich KRAS mRNA. In preclinical models of sotorasib-resistant lung cancer, METTL13 loss restored drug sensitivity and extended survival without harming normal cells.

eEF1A methylation and decoding speed

• ▪Methylation of eEF1A by METTL13 equalizes decoding rates between fast and slow codons, removing the natural translation brake and enabling rapid synthesis of KRAS protein.
• ▪Single-molecule imaging tracking individual ribosomes in real time confirmed that codon-decoding speed depends on eEF1A methylation at the lysine-55 site.
• ▪METTL13 functions as a protein methyltransferase that attaches methyl groups to the ribosomal delivery protein eEF1A at lysine 55, forming modified eEF1AK55me2.

Codon bias in KRAS translation

• ▪KRAS messenger RNA is rich in slowly decoded wobble-position codons that under normal conditions act as a natural brake on KRAS protein output.
• ▪Replacing wobble-heavy KRAS codons with synonymous codons eliminated the reduction in KRAS protein caused by METTL13 knockout in experimental cell models.
• ▪METTL13 activity selectively enhances the translation of codon-biased cancer transcripts without broadly suppressing the synthesis of housekeeping proteins encoded by efficiently decoded mRNAs.

Overcoming resistance to KRAS inhibitors

• ▪Higher METTL13 activity in tumor samples from patients with KRAS-mutant lung, pancreatic, and colorectal cancers correlates with poor prognosis and reduced responsiveness to KRAS inhibitors.
• ▪In preclinical models of sotorasib-resistant KRAS-mutant lung cancer, METTL13 loss slowed tumor growth, restored sensitivity to sotorasib, and significantly extended survival.
• ▪Approved targeted drugs like sotorasib and adagrasib inhibit mutant KRAS directly, but tumors routinely adapt and develop resistance within months.

The Nature Cell Biology study

• ▪A study identified the METTL13 enzyme as an upstream driver of KRAS protein overproduction
• ▪Funding for the Nature Cell Biology study was provided by the National Cancer Institute, the American Cancer Society, MD Anderson Cancer Center, and St. Jude Children's Research Hospital.

Selectivity and safety in normal cells

• ▪The FDA approved tazemetostat in 2020 as an EZH2 methyltransferase inhibitor, establishing proof of concept that targeting epigenetic writers can spare normal tissues.
• ▪Research in the model organism Caenorhabditis elegans published in eLife demonstrated that knocking out METTL13 produces no toxicity in normal, non-cancerous cells.

Future METTL13 drug development

• ▪The next phase of research involves developing selective METTL13 inhibitors to test alongside sotorasib or adagrasib in combination therapy models.
• ▪No clinical-stage small-molecule inhibitor targeting METTL13 has entered clinical trials as of October 2026.