Scientists at the UT Southwestern Children’s Medical Center Research Institute in Dallas, Texas (USA) have discovered a new metabolic vulnerability in a particularly aggressive type of non-small cell lung cancer, which which could be used for the development of future treatments in patients with mutations in two key genes, KRAS and LKB1, the prognosis is serious, as they also do not respond to immunotherapy.
“We used to think that most tumors depend on the same set of metabolic pathways to grow, but in the last decade we’ve learned that this is an oversimplification,” explains one of the study’s researchers, Ralph DeBerardinis. In contrast, he adds, different tumor subclasses have particular metabolic needs that arise from mutations in key genes. “Understanding how specific combinations of mutations promote tumor growth and metastasis can allow us to design therapies tailored to patients,” he says, about the possible contribution of these findings to precision medicine.
While it was already known that mutations in KRAS or LKB1 can alter metabolism individually, 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 containing different mutations and with the normal lung.
Thus, during the study, recently published in ‘Nature Metabolism’, scientists discovered that the hexosamine biosynthesis pathway is activated in KL tumors. These findings were consistent thanks to previous research in the DeBerardinis laboratory, which showed that KL cells reprogram carbon and nitrogen metabolism. In this way, they grow, but also increase their sensitivity to particular metabolic inhibitors.
THE PROCESS OF Glycosylation
The hexosamine biosynthesis pathway allows cells to modify proteins through a process called glycosylation, which facilitates the transit and secretion of proteins. Specifically, it is believed that the high rate of protein production that fuels KL tumor growth requires activation of the hexosamine biosynthesis pathway.
Therefore, in order to develop ways to inhibit this pathway, the researchers identified the enzyme GFPT2 as a key culprit in KL tumors. Thus, genetic silencing or chemical inhibition of this enzyme suppressed the growth of KL tumors in mice, but had little effect on the growth of tumors containing only the KRAS mutation. Taken together, the findings indicate the selective importance of the hexosamine biosynthesis 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,” explained the postdoctoral fellow who led the study with DeBerardinis, Jiyeon Kim, on future prospects. “In the end, we are looking for options that can help stop the growth and spread of these aggressive tumors,” he concludes.