Scientists at the Research Institute at UT Southwestern Children’s Medical Center in Dallas, Texas (United States) have discovered a new metabolic vulnerability in a particularly aggressive form of non-small cell lung cancer that can be used to develop future treatments in patients with mutations in two key genes, KRAS and LKB1, of which the prognosis is severe, as they are also unresponsive to immunotherapy.
“We used to think that most tumors depend on the same metabolic pathways to grow, but over the past decade we’ve learned that this is too simple a simplification,” explains one of the study’s researchers, Ralph DeBerardinis. On the contrary, he adds, different subclasses of tumors have specific metabolic needs arising from mutations in key genes. “Understanding how specific combinations of mutations promote tumor growth and metastasis can help tailor therapies to patients,” he says of the potential contribution of these findings to precision medicine.
While it was already known that mutations in KRAS or LKB1 can individually alter metabolism, less was known about metabolic needs when both genes are mutated in the same tumor. To discover new metabolic deficiencies, the scientists compared the properties of genetically engineered KL tumors in mice with tumors with different mutations and with the normal lung.
For example, during the research, recently published in ‘Nature Metabolism’, the scientists discovered that the hexosamine biosynthesis pathway is activated in KL tumors. These findings were consistent thanks to previous research in DeBerardinis’ lab, which showed that KL cells reprogram carbon and nitrogen metabolism. In this way, they grow, but they also increase their sensitivity to certain metabolic inhibitors.
THE GLYCOSILATION PROCESS
The hexosamine biosynthetic pathway allows cells to modify proteins through a process called glycosylation that facilitates the trade and secretion of proteins. In particular, the high rate of protein production that stimulates the growth of KL tumors is believed to require activation of the hexosamine biosynthetic pathway.
Therefore, to develop ways to inhibit this pathway, the researchers identified the enzyme GFPT2 as a major culprit in KL tumors. Gene silencing or chemical inhibition of this enzyme thus suppressed the growth of KL tumors in mice, but had little effect on the growth of tumors containing only the KRAS mutation. In summary, the findings indicate the selective importance of the hexosamine biosynthetic pathway in KL tumors and suggest that GFPT2 could be a useful target for this aggressive subtype of non-small cell lung cancer.
“Since there is no specific inhibitor against GFPT2, our next step is to see if blocking certain steps in the glycosylation pathway could be therapeutically beneficial,” explains postdoctoral fellow Jiyeon Kim, who led the study with DeBerardinis. future prospects. “Ultimately we are looking for options that can help stop the growth and spread of these aggressive tumors,” he concludes.