Possible Treatment Identified for Aggressive NSCLC Subset

A potential treatment for patients with non–small cell lung cancer (NSCLC) with KRAS and LKB1 mutations was discovered by researchers from the Children’s Medical Center Research Institute at the University of Texas Southwestern (CRI).¹ Tumors with both mutations, known as KL tumors, are highly aggressive, and patients who have them usually do not respond to immunotherapy.

Individually, KRAS and LKB1 mutations can alter a patient’s metabolism and response to treatment. However, when both genes are mutated in the same tumor, the exact ways in which they promote tumor growth and metastasis are not yet clear. But the recent study from the CRI found that inhibiting the hexosamine biosynthesis pathway (HBP), which allows cells to modify proteins, could be a potential treatment in those types of tumors.²

"We used to think that most tumors rely on the same handful of metabolic pathways to grow, but we've learned over the last decade that this is an oversimplification. Instead, different tumor subclasses have particular metabolic needs arising from mutations in key genes,” study author Ralph DeBerardinis, MD, PhD, a professor at CRI and a Howard Hughes Medical Institute investigator, said in a statement. “Understanding how specific combinations of mutations promote tumor growth and metastasis may allow us to design tailored therapies for patients."

In the study that led to the findings, published in Nature Metabolism, the researchers compared the metabolic properties of genetically engineered KL tumors in mice with tumors with different mutations and with a normal lung. They found that in KL tumors, the HBP was activated. This is in line with previous research from the Ralph DeBerardinis Laboratory showing that KL cells reprogram carbon and nitrogen metabolism, promoting growth but increasing their sensitivity to certain inhibitors.³

KL tumor growth is fueled by a high rate of protein production, which is thought to require HBP activation. To inhibit that pathway, researchers targeted GFPT2, which they identified as a liability in KL tumors. Targeting GFPT2 did not have much effect on tumors with KRAS mutations alone, but it did suppress KL tumor growth in the mouse models. These findings suggest that GFPT2 could be a useful target in NSCLC with KRAS and LKB1 mutations.

Currently, there is no GFPT2 inhibitor, so researchers aim to look into blocking steps along the pathway, said Jiyeon Kim, PhD, the postdoctoral fellow who led the study with DeBerardinis.

"Since no specific inhibitor against GFPT2 exists, our next step is to see if blocking certain steps in the glycosylation pathway could be therapeutically beneficial,” Kim said. “Ultimately we are looking for options that can help stop the growth and spread of these aggressive tumors."

References

1. Researchers uncover a potential treatment for an aggressive form of lung cancer. News release. Children’s Medical Center Research Institute at UT Southwestern; January 5, 2021. Accessed January 8, 2021. https://www.utsouthwestern.edu/newsroom/articles/year-2021/aggressive-form-of-lung-cancer.html

2. Kim J, Lee HM, Cai F, et al. The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer. Nat Metab. Published online November 30, 2020. doi:10.1038/s42255-020-00316-0

3. Kim J, Hu Z, Cai L, et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature. Published online May 24, 2017. doi:10.1038/nature22359