A find opens the door to the treatment of …

A team of American scientists succeeded in finding a new metabolic vulnerability in a type of lung cancer non-small cell which is particularly aggressive. This discovery could be used for the development of future treatments in patients with mutations in two key genes, KRAS and LKB1, whose prognosis is serious because they do not respond to immunotherapy.

“We used to think that most tumors depend on the same set of metabolic pathways to grow, but over the past decade we’ve learned that this is an oversimplification,” says Ralph. DeBerardinis, one of the authors of the study conducted by the Institute. Research Department at UT Southwestern Children’s Medical Center in Dallas, Texas, USA.

DeBerardinis points out that different tumor subclasses have unique metabolic needs that result from mutations in key genes. “Understanding how specific combinations of mutations promote tumor growth and metastasis can allow us to tailor therapies to patients,” he adds.

While the scientific community was aware that mutations in KRAS or LKB1 can individually alter metabolism, little was known about metabolic needs when both genes are mutated in the same tumor.

In order to find new metabolic deficiencies, the experts compared the properties of genetically modified KL tumors in mice with tumors with different mutations and with normal lungs.

In research recently published in “Nature Metabolism”, specialists came to the conclusion that the hexosamine biosynthetic pathway is activated in KL tumors.

The consistency of these results is also supported by studies previously conducted in DeBerardinis’ lab, which showed that KL cells reprogram carbon and nitrogen metabolism, which implies that they grow, but also increase their sensitivity to certain metabolic inhibitors.

The glycosylation process

The hexosamine biosynthetic pathway allows cells to change proteins through a process called glycosylation, which facilitates the trafficking and secretion of proteins. At present, the high rate of protein production that fuels the growth of KL tumors is believed to require activation of the hexosamine biosynthetic pathway.

In order to develop ways to inhibit this pathway, the researchers attempted to identify the enzyme GFPT2, one of the main culprits of KL tumors. What they found was that genetic silencing or chemical inhibition of this enzyme suppressed the growth of KL tumors in mice, although this had little effect on the growth of tumors that contained only the KRAS mutation.

Ultimately, these results underscored the selective importance of the hexosamine biosynthetic pathway in KL tumors and suggest that GFPT2 may 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 beneficialSays Jiyeon Kim, a postdoctoral fellow who led the study. “Ultimately, we’re looking for options that can help stop the growth and spread of these aggressive tumors,” he concludes.