A new study reveals that oncogenic signaling can reshape cancer cells not only by changing gene activity, but also by changing how cellular machinery reads the genetic code.
Cancer cells are highly adaptable. Mutations that activate the RAS-MAPK signaling pathway—one of the most common cancer-driving mechanisms—allow tumors to grow aggressively and often make them resistant to targeted therapies. For decades, scientists have viewed RAS mainly as a signaling switch that controls gene expression through phosphorylation cascades.
Now, a collaborative team led by Fei Lan and Jiabing Cai at Fudan University and Zhongshan Hospital, Shanghai, China, has uncovered an unexpected layer of RAS-driven cancer regulation: oncogenic RAS can reprogram the way ribosomes read genetic information during protein synthesis.
The study, published in Vita, reveals that RAS signaling creates a specialized “codon-defined translational program” that selectively boosts production of proteins required for tumor growth and drug resistance.

RAS removes a hidden bottleneck in protein production
The genetic code is often viewed as a simple instruction system in which three-letter nucleotide sequences, called codons, specify amino acids. However, not all codons are translated equally efficiently. Some rare codons act as natural speed bumps that slow down ribosomes during protein production.
One such codon is CGA, which encodes the amino acid arginine. Because CGA is relatively inefficiently decoded, it can create a bottleneck during translation. These built-in pauses are not random: many genes enriched in CGA codons encode important cellular regulators, including proteins involved in ribosome production, RNA processing, and cell-cycle control.
The researchers asked whether cancer-driving signals could influence these codon-level translation barriers.
By comparing multiple oncogenic pathways, including activated RAS, MYC overexpression, and PTEN loss, the team discovered that RAS activation produced a unique effect: it specifically relieved the translation bottleneck at CGA codons. As a result, CGA-enriched genes were translated more efficiently, increasing production of proteins that help cancer cells proliferate and survive.
Importantly, different oncogenic pathways appeared to use different codon-level strategies. While RAS preferentially affected CGA decoding, MYC activation or PTEN loss showed distinct codon signatures, suggesting that cancer cells may use diverse “translation programs” depending on their genetic drivers.

A molecular switch connects RAS signaling to codon-specific translation
The study further revealed how RAS signaling controls this hidden translational layer.
The researchers identified METTL13, a methyltransferase that modifies the translation elongation factor eEF1A, as the key molecular regulator of CGA decoding. When RAS signaling is activated, the downstream kinase RSK phosphorylates METTL13 at a specific site, increasing METTL13 activity.
Activated METTL13 enhances dimethylation of eEF1A at lysine 55, which improves the ability of the translation machinery to efficiently deliver the CGA-decoding tRNA to ribosomes. This allows ribosomes to overcome the CGA bottleneck and increase production of CGA-enriched proteins.
“This finding reveals that oncogenic signaling can influence not only which genes are expressed, but also how the genetic code itself is interpreted,” said by Dr. Lan, professor Fudan University.
Targeting a translational vulnerability to overcome drug resistance
The therapeutic implications of this discovery were tested in patient-derived tumor organoids and cancer models.
RAS inhibitors can initially suppress tumor growth, but resistant cancer cells often emerge and drive disease recurrence. The researchers found that these drug-tolerant cells retained high activity of the METTL13–eEF1A pathway and maintained efficient CGA decoding.
Blocking METTL13 disrupted this translational dependency, reduced the survival of resistant cancer cells, and enhanced the response to RAS pathway inhibitors in multiple tumor models.
Unlike approaches that globally inhibit protein synthesis, which can affect many normal tissues, targeting a cancer-specific translational program may provide a more selective strategy. The study suggests that METTL13 and CGA-dependent translation could represent potential vulnerabilities in RAS-driven cancers, although further development of selective METTL13 inhibitors and clinical biomarkers will be required.

A new view of how cancer rewires biology
This study expands the traditional view of oncogenic signaling. Cancer cells do not only alter transcriptional programs or signaling networks—they can also modify the fundamental process by which ribosomes interpret genetic information.
The discovery of a RAS-controlled codon-selective translation program suggests that the genetic code itself contains regulatory information that cancer cells can exploit. Just as transcription factors recognize specific DNA sequences to control gene expression, signaling pathways may influence how ribosomes decode specific codons to reshape the proteome.
By revealing this previously unrecognized connection between oncogenic signaling and the translation machinery, the study opens a new avenue for understanding cancer biology and developing precision therapies that target tumor-specific vulnerabilities at the level of protein synthesis.
DOI: 10.15302/vita.2026.07.0049