Researchers at the Children’s Medical Center Research Institute at UT Southwestern (CRI), USA, have discovered a new metabolic vulnerability in a highly aggressive form of non-small cell lung cancer (NSCLC). These findings could pave the way for new treatments for patients with mutations in two key genes — KRAS and LKB1. Patients whose tumours contain both of these mutations, known as KL tumours, have poor outcomes and usually do not respond to immunotherapy.
“We used to think that most tumours 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 tumour subclasses have particular metabolic needs arising from mutations in key genes. Understanding how specific combinations of mutations promote tumour growth and metastasis may allow us to design tailored therapies for patients,” says Ralph DeBerardinis, M.D., Ph.D., a professor at CRI and a Howard Hughes Medical Institute investigator.
While mutations in either KRAS or LKB1 can alter metabolism individually, less is known about the metabolic needs when both genes are mutated in the same tumour. To uncover new metabolic vulnerabilities, the scientists compared metabolic properties of KL tumours genetically engineered in mice to tumours containing different mutations and to the normal lung. In the study, published recently in Nature Metabolism, they discovered that the hexosamine biosynthesis pathway (HBP) is activated in KL tumours. These findings were consistent with previous research in the DeBerardinis lab that showed KL cells reprogram carbon and nitrogen metabolism in ways that promote their growth but increase their sensitivity to particular metabolic inhibitors.
The HBP allows cells to modify proteins through a process called glycosylation, which facilitates protein trafficking and secretion. The high rate of protein production that fuels KL tumour growth is thought to require activation of the HBP. In order to develop ways to inhibit the HBP, the researchers next identified the enzyme GFPT2 as a key liability in KL tumours. Genetically silencing or chemically inhibiting this enzyme suppressed KL tumour growth in mice, but had little effect on the growth of tumours containing only the KRAS mutation. Altogether, the findings indicate the selective importance of the HBP in KL tumours and suggest that GFPT2 could be a useful target for this aggressive subtype of NSCLC.
“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. Ultimately we are looking for options that can help stop the growth and spread of these aggressive tumours,” says Jiyeon Kim, Ph.D., the postdoctoral fellow who led the study with DeBerardinis. Kim is now an assistant professor in the department of biochemistry and molecular genetics at the University of Illinois at Chicago.
Paper: Jiyeon Kim, Hyun Min Lee, Feng Cai, Bookyung Ko, Chendong Yang, Elizabeth L. Lieu, Nefertiti Muhammad, Shawn Rhyne, Kailong Li, Mohamed Haloul, Wen Gu, Brandon Faubert, Akash K. Kaushik, Ling Cai, Sahba Kasiri, Ummay Marriam, Kien Nham, Luc Girard, Hui Wang, Xiankai Sun, James Kim, John D. Minna, Keziban Unsal-Kacmaz, Ralph J. DeBerardinis. The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1 mutant lung cancer. Nature Metabolism, 2020; 2 (12): 1401 DOI: 10.1038/s42255-020-00316-0
Source: UT Southwestern Medical Center