Dr. Gina DeNicola and Dr. Lewis Cantley
Photo credit: Kristin Gladney
The classic role of the gene nuclear factor erythroid-2-related like 2, or NRF2, is to promote the production of the body’s natural antioxidants, or chemicals that help prevent cell damage. In a study published Oct. 19 in Nature Genetics, Weill Cornell Medicine scientists discovered that the mutated gene plays a crucial role in lung cancer cells’ metabolism — how the cancer converts sugar, or glucose, into amino acids that act as building blocks for proteins and other molecules — driving tumor growth. They say this discovery could offer a new target to effectively treat the disease.
“We could potentially treat this with an inhibitor that targets the pathway,” said lead author Dr. Gina DeNicola, a research fellow and member of the lab of Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “This would be a big boost for non-small cell lung cancer, which typically has a poor prognosis. Patients are often resistant to traditional chemotherapy and radiation treatments, and so far few therapies have really shown much promise.”
Non-small cell lung cancer is a disease widely associated with smoking and exposure to other pollutants and chemicals such as radon and asbestos. It accounts for 85 to 90 percent of all lung cancers, which cumulatively kill about 158,040 Americans each year.
In their study, Dr. DeNicola, Dr. Cantley — who owns equity in, receives compensation from and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals — and colleagues Edouard Mullarky and David Wu discovered that mutations in the NRF2 gene and an associated gene called KEAP1 (Kelch-Like ECH-Associated Protein 1, which in normal cells inhibits antioxidant production) lead to increased production of several enzymes, including phosphoglycerate dehydrogenase (PHGDH).
These enzymes boost production of the amino acid serine and its conversion to glycine, another important building block. Together, serine and glycine are critical to producing proteins and other molecules, including an antioxidant, that help NSCLC to thrive. The series of events involved in this process is called the serine/glycine biosynthetic pathway.
While directly targeting the NRF2 gene with drugs would be challenging, developing drugs that interrupt other points of the serine/glycine biosynthetic pathway may be possible, Dr. DeNicola said.
“Targeting the pathway could be a way of attacking these cells that have NRF2 and KEAP1 mutations,” she said.
Developing drugs that inhibit PHGDH may be promising because the enzyme is one of the first on the pathway and would stop subsequent actions promoting cancer. To test this theory, Dr. DeNicola and the research team silenced PHGDH in NSCLC cells in cultures and in mice, and found that the cells did not grow or multiply.
About four years ago, the Cantley Lab found that PHGDH enzyme levels are high in melanoma and triple negative breast cancer. Unlike NSCLC, these high levels were due to the large number of PHGDH gene copies in cancer cells. However, the PHGDH enzyme also contributed to events on the serine/glycine biosynthetic pathway.
While the ways in which the serine/glycine biosynthetic pathway are turned on in NSCLC and melanoma and triple negative breast cancer differ, finding a way to target the pathway could be beneficial for all of these diseases, Dr. DeNicola said. The findings may also be applicable to other malignancies in which NRF2 levels are high, such as pancreatic cancer.
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