New study identifies potential targets for KRAS-related treatment resistance

Decoding of messenger RNA (mRNA) occurs during translation, the vital cellular process that builds proteins. Errors in this process are known to lead to cancer growth. Scientists at St. Jude Children's Research Hospital identified how one factor involved in mRNA decoding can be altered, identifying potential cancer origins and new targets for KRAS-related treatment resistance. The results were published today in Nature Cell Biology. 

To add the correct building block to a protein, the ribosome (the molecular machine that makes proteins) reads codons (a grouping of three nucleotides) in a process called mRNA decoding during translation elongation. The translation elongation factor eEF1A influences the speed and accuracy of mRNA decoding. It was known that, in certain tumors, the METTL13 enzyme modifies eEF1A at lysine 55 (eEF1AK55me2), thus increasing protein synthesis and promoting tumor growth. How eEF1AK55me2 affects translation elongation and contributes to tumor growth was unknown. 

We worked collaboratively with our co-authors to create cell lines that lacked METTL13 to recombinantly express eEF1 with and without METTL13-mediated methylation. We then leveraged the power of parallelized single-molecule imaging experiments to demonstrate that eEF1AK55me2 affects mRNA decoding in a way that rationalized our collaborators' observations in quantitative, kinetic and structural terms." 

Scott Blanchard, PhD, co-corresponding author, St. Jude Department of Structural Biology

Solving the eEF1AK55me2-METTL13 axis 

The work built upon findings from a study the St. Jude team published in Nature in 2023, in which they used cryo-electron microscopy to determine the atomic structure of human ribosomes bound to eEF1A and compared mRNA decoding in human and bacterial translation. That study created a foundation to examine the effect of the eEF1AK55me2-METTL13 axis on translation. 

Through proteomic profiling and single-molecule imaging, the team found that the axis promotes efficient translation of a subset of codons that are enriched in oncogenes, such as KRAS. Because KRAS is an oncogenic driver present in many tumor types, understanding how it is expressed and how it develops resistance to standard-of-care treatments is of interest to the oncology field. The team further examined METTL13 disruption as a potential target to overcome KRAS-related treatment resistance and observed stymied growth of KRAS-inhibitor–resistant tumors in animal models. 

These findings have implications for developing future treatment strategies in which METTL13 could be used as a target to inhibit KRAS production in tumors. In healthy pre-clinical models, it was found that knocking out METTL13 does not cause toxic effects, a significant positive feature for potential clinical use. 

"Our team's research demonstrates that this methyltransferase stimulates the translation of KRAS and other proliferation-promoting proteins. Reducing KRAS production, a known driver of many cancers, can be achieved by knocking down METTL13 using a drug or some other mechanism, so that KRAS-driven cancer patients can have a better chance of survival," said Blanchard. 

Varying elongation rates have critical impact 

The team also discovered that the speed of elongation varies, with critical impacts on protein production. 

"There is a growing understanding that protein synthesis occurs at rates that are not uniform. In our findings, we showed that even two related codons, encoding the same amino acid but differing in the third nucleotide position, can show different decoding speeds in a manner that depends on eEF1A K55 methylation," said Blanchard. "When METTL13 is present and eEF1A K55 is methylated, the two related codons are decoded at very similar rates; when METTL13 is absent, the codons are decoded at different rates." 

The presence of METTL13 as a possible prognostic tool 

To examine how the presence of METTL13 influenced other aspects of cancer development, the team examined its effect on patient prognosis. They compared pre-clinical models in which METTL13 disruption prevented tumor growth with outcome data from patients with lung adenocarcinoma and pancreatic ductal adenocarcinoma, tumors in which METTL13 is often amplified. They observed that increased methyltransferase activity correlated with poor prognosis. 

"We found that you can look for the activity of this methyltransferase in cancer, because high activity of METTL13 seems to correlate with aggressive cancer and lower survival," said co-first author Aaron Cruz-Navarrete, PhD, St. Jude Department of Structural Biology. "Our results show there's a potential to use the activity of this methyltransferase as a prognostic tool."