In a recent study published in the journal Proceedings of the National Academy of Sciences, a team of researchers from the Salk Institute have discovered that a mutated enzyme, called EphA2, leads to the quick growth of a type of lung cancer in humans.
The EphA2 enzyme is known to control a gene that is responsible for tissue growth. However, in the new study the researchers found that when this enzyme is mutated it leads to an aggressive development of tumors. Based on the new findings, researchers suggest that EphA2 could be a target for a type of lung cancer that affects both smokers and non-smokers and is the leading cause of deaths related to cancer worldwide.
“Sometimes there are hundreds of mutations in the genes of a patient’s tumors, but you don’t know whether they are drivers of the disease or byproducts,” said senior author Inder Verma, professor of genetics and holder of Salk’s Irwin and Joan Jacobs Chair in Exemplary Life Science, in a recent news release. “We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies.”
There are two gene mutations that cause the development of human tumors, specifically, mutations in the genes p53 and KRAS. However, these gene mutations are difficult to target in current standard treatments. Because of this, the team of researchers decided to study the genes that are thought to regulate p53 and KRAS.
The scientists focused on the 4,700 genes found in the human genome associated with cellular signaling (genes that tamp down cell development and spread). The researchers then used an adapted version of a genetic screening method to examine the effect of these genes on tumor development. Using animal models, the scientists discovered that 16 of these cell-signaling genes formed molecules which had a significant effect on p53 and KRAS-related tumors.
Of these, the EphA2 enzyme stood out. The enzyme was first discovered in the lab of Tony Hunter, also a researcher at the Salk Institute, but its importance in lung cancer was not fully understood at that time. In this study, researchers found that the absence of EphA2 allowed for a much more aggressive growth of the KRAS-related tumors.
“With a mutation in KRAS, a tumor forms in 300 days. But without EphA2, the KRAS mutation leads to tumors in half the time, 120 to 150 days,” said Dr. Verma, who is also an American Cancer Society Professor of Molecular Biology. “This molecule EphA2 is having a huge effect on restraining cancer growth when KRAS is mutated.” Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and lung cancer.
“Since activating EphA2 led to the suppression of both cell signaling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,” said Narayana Yeddula, a Salk research associate and first author of the paper.
A 10-year national research project called the Cancer Genome Atlas mapped hundreds of patients’ genomes for more than 20 different cancers and found a number of associated gene mutations. However, the role of these gene mutations remains poorly understood in lung cancer (particularly adenocarcinoma, a type of cancer representing about a quarter of all lung cancers).
Using data from this large project, the researchers discovered that EphA2 gene alterations were identified in 54 cases of a total of 230 adenocarcinoma patients. The researchers also discovered that the absence of EphA2 activated a signaling pathway typically related to cancer and that stimulates tumor growth.
“Oddly, among human lung cancer patients with EphA2 mutations, around 8 percent of patients actually have high EphA2 expression. So, in some instances, EphA2 is not suppressing tumors and may be context-dependent. Therefore, we need to carefully evaluate the molecule’s function when designing new therapeutics,” added Yifeng Xia, a Salk staff researcher.
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