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A Metabolic Pathway Driving Growth of Aggressive Lung Cancers

Gallagher, Amy

doi: 10.1097/01.COT.0000749936.14046.87
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Ralph DeBerardinis, MD, PhD
Ralph DeBerardinis, MD, PhD:
“In the past, we believed that most tumors rely on the same handful of metabolic pathways to grow, but now we know that is an oversimplification. Different tumor subclasses have particular metabolic needs, some of which arise from mutations in key genes,” stated Ralph DeBerardinis, MD, PhD, CRI Professor of Pediatrics; Chief of the Division of Pediatric Genetics and Metabolism, and investigator, Howard Hughes Medical Institute.

While molecular targets have been identified to improve treatment of non-small cell lung cancer (NSCLC), the 5-year overall survival rate remains at 16 percent. Understanding the molecular mechanisms of NSCLC progression remains at the forefront for researchers in pursuit of innovative therapies to treat the disease.

As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with small cell lung cancer, according to the National Cancer Institute, emphasizing the need for better treatments.

Research conducted at the Children's Medical Center Research Institute (CRI) at UT Southwestern discovered a new metabolic vulnerability in a highly aggressive form of NSCLC generating the potential for new treatments for NSCLC patients with mutations in two key genes—the oncogene KRAS and the tumor suppressor gene STK11, which encodes the kinase LKB1.

Both genes regulate metabolism and tumors with mutations in both are particularly aggressive, said Ralph DeBerardinis, MD, PhD, CRI Professor of Pediatrics; Chief of the Division of Pediatric Genetics and Metabolism, and investigator at the Howard Hughes Medical Institute.

“In the past, we believed that most tumors rely on the same handful of metabolic pathways to grow, but now we know that is an oversimplification,” said DeBerardinis. “Different tumor subclasses have particular metabolic needs, some of which arise from mutations in key genes.”

Genes in KL Tumors Mutate More Aggressively

Metabolism is dynamic and responds to many different cellular processes. “This predicts that aggressive tumors have metabolic properties not present in less aggressive tumors,” said DeBerardinis.

Because KL tumors [tumors with mutations in both KRAS and LKB1] are so aggressive, the researchers sought metabolic differences between these tumors, tumors with only one of the two mutations, and healthy lungs in patients and mouse models of cancer.

“Understanding how specific mutations or combinations of mutations promote tumor growth and metastasis may allow us to design tailored therapies for patients,” said DeBerardinis.

Asked whether metabolic pathways affect tumor growth and metastasis in the same way, he confirmed in the negative.

“We are still learning which metabolic pathways stimulate tumor growth,” he noted. “But we know much less about which pathways allow cells to metastasize. The data so far tell us that some pathways are more important for metastasis than for tumor growth at the original site. KL tumors metastasize frequently, so we need to understand how their metabolism differs from other lung cancers.”

Metabolic Vulnerability in KL Lung Cancer

The DeBerardinis lab noticed that metabolites involved in the hexosamine biosynthesis pathway (HBP) are particularly elevated in KL tumors, both in patients and mice.

“The HBP allows cells to modify proteins for trafficking to the cell membrane or secretion,” said DeBerardinis. “The high rate of protein production that fuels KL tumor growth is thought to require activation of the HBP.”

These findings were consistent with previous research conducted in the DeBerardinis Laboratory, which identified changes in nitrogen metabolism that promote KL tumor growth, but increase their susceptibility to inhibitors that block these pathways. “Activating the HBP also induces a change in the way these tumors use nitrogen,” he said. In addition to supporting cell growth, the HBP is also involved in cell adhesion and migration, possibly signaling a link to metastasis.

Enzyme as Key Liability in KL Tumors

In order to develop ways to inhibit the HBP, the researchers next identified the enzyme GFPT2 as a key liability in KL tumors.

“This was surprising because both GFPT2 and a related enzyme, GFPT1, are present in KL tumors,” said DeBerardinis. “But genetically silencing or chemically inhibiting GFPT2 suppressed KL tumor growth in mice.” GFPT2 blockade had no effect on the growth of tumors containing only the KRAS mutation.

“Altogether, the findings indicate the selective importance of the HBP in KL tumors and suggest that GFPT2 could be a useful target for this aggressive subtype of NSCLC,” he stated. This is encouraging because if other cells in the body can use GFPT1, they may tolerate inhibition of GFPT1, which warrants further study, he said.

“Since no specific inhibitor against GFPT2 exists yet, our next step is to see if blocking other steps in the glycosylation pathway could be therapeutically beneficial,” said Jiyeon Kim, PhD, who led the study with DeBerardinis, and is Assistant Professor in the Department of Biochemistry and Molecular Genetics at the University of Illinois Chicago. “Ultimately we are looking for options that can help stop the growth and spread of these aggressive tumors.”

Amy Gallagher is a contributing writer.

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