Newly found enzyme pathway helps cancer cells churn out KRAS growth proteins

Scientists at The University of Texas MD Anderson Cancer Center have identified a previously unknown mechanism that helps cancer cells selectively manufacture the proteins that drive tumor growth, including KRAS, one of the most commonly mutated cancer genes. The study, published in Nature Cell Biology and co-led by Pawel Mazur, Ph.D., associate professor of Experimental Radiation Oncology, shows that an enzyme called METTL13 gives cancer cells a production advantage for a specific subset of growth-promoting proteins. Blocking or removing that enzyme slowed tumor growth in preclinical models and, in some cases, restored sensitivity to KRAS-targeted drugs that had stopped working.

The mechanism centers on how efficiently the protein-building machinery of the cell reads messenger RNA. Many cancer-driving genes, including KRAS, produce large amounts of messenger RNA rich in particular strings of genetic “words” known as codons, which serve as the instructions for assembling proteins. Structural, chemical and metabolic barriers can make it harder for the protein-producing machinery to read those codons. The researchers found that METTL13 adds a small chemical tag, a methylation mark, to one of the proteins involved in protein production itself. That modification helps cancer cells read the codons more efficiently, allowing them to produce larger amounts of the proteins that promote tumor growth.

Importantly, the effect was selective rather than global. METTL13 did not broadly increase the production of all proteins in the cell; instead, it preferentially enhanced the output of only a subset of proteins, many of which are involved in cancer growth and survival. “Our findings show that, in cancer cells, the METTL13 enzyme facilitates the production of important growth-driving proteins,” Mazur said. “By understanding the underlying mechanisms and removing that support, we may be able to make tumors more vulnerable to treatment and help improve patient outcomes.”

The therapeutic implications were tested in several preclinical cancer models. Reducing or removing METTL13 lowered levels of KRAS and other cancer-driving proteins and slowed tumor growth. In KRAS-mutant lung cancer models, including tumors that had already developed resistance to the KRAS inhibitor sotorasib, the loss of METTL13 slowed tumor growth, restored treatment sensitivity and significantly extended survival. The researchers also observed that patients whose tumors had higher METTL13 activity tended to have poorer responses to KRAS inhibitors, an association that further suggests the pathway plays a role in treatment resistance.

Current KRAS inhibitors work by blocking the KRAS protein only after it has already been produced. The new findings point to a possible way to intervene earlier in the process, by targeting METTL13 and limiting how much KRAS protein cancer cells produce in the first place. The findings suggest the enzyme could be a target for KRAS-driven cancers, which include many lung and pancreatic cancers. Although KRAS-targeted therapies have improved outcomes for some patients, tumors often adapt and become resistant over time, making strategies that attack the supply chain of the protein rather than the protein itself an attractive direction for further study.

The researchers caution that the results so far are preclinical and require further validation before they can be translated into the clinic. The team is now working to better understand how METTL13 controls protein production and to develop strategies for safely targeting the enzyme. Future studies will also investigate whether the level of METTL13 activity in a tumor could help predict which patients are most likely to benefit from KRAS-targeted therapy. The work was funded in part by the National Institutes of Health, the Terry Fox Foundation Oncometabolism Team, the Swedish Cancer Society, the Wallenberg Academy, the Cancer Research Foundations of Radiumhemmet, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas, and the American Cancer Society.

Subject of Research: The role of the METTL13 enzyme in selectively producing KRAS and other cancer-driving proteins and its potential as a therapeutic target.

Article Title: Newly discovered pathway fuels production of cancer-driving proteins

Article References: Newly discovered pathway fuels production of cancer-driving proteins. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: METTL13, KRAS, cancer biology, protein synthesis, methylation, treatment resistance, sotorasib, lung cancer, pancreatic cancer, preclinical models, MD Anderson Cancer Center, Nature Cell Biology