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Molecular Brake Stifles Human Lung Cancer

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A new research published recently in PNAS has revealed that researchers at the Salk Institute have uncovered a molecule whose mutation leads to the aggressive growth of a common and deadly type of lung cancer in humans.  The molecule they have discovered is an enzyme called EphA2 and it typically polices a gene that is responsible for tissue growth. The team of researchers at Salk discovered that when EphA2 is mutated, the cellular systems run hither and thither and quickly develop tumors. The study also suggests that EphA2 could be a new focus for a subset of lung cancer, which affects nonsmokers as well as smokers, and is the leading cause of cancer-related deaths worldwide.

Inder Verma, senior author of the study, professor of genetics and holder of Salk’s Irwin and Joan Jacobs Chair in Exemplary Life Science said that sometimes there are hundreds of mutations in the genes of a patient’s tumors, but it is not known whether they are drivers of the disease or byproducts. Through this research they have found a new way which can aid to identify cancer suppressor genes and understand how they could be targeted for therapies.

It is known that KRAS and p53 are the two gene mutations that are responsible to spur the growth of human tumors. Even though there have been a lot of studies on both these genes, they are quite difficult to target therapeutically. Hence, the research team at Salk decided to look at genes that might police KRAS and p53.

For the study, the team focused on the 4,700 genes in the human genome related to cellular signaling”particularly the ones that can tamp down cell growth and proliferation. The team adapted a genetic screening technique to efficiently test the effect of these thousands of genes on the development of tumor. It was found by the Salk team that in animal models 16 of these cell-signaling genes produced molecules that substantially affected KRAS- and p53-related tumors. Of the 16, the EphA2 enzyme was the one that stood out. EphA2’s significance in lung cancer has not been not clearly understood till date, but the team found that when it was absent, the KRAS-related tumors flourished.

Verma remarked that typically when a mutation occurs in KRAS, a tumor is formed in 300 days. However, in absence of EphA2, the KRAS mutation leads to tumors in just 120 to 150 days. This confirms one thing – EphA2 does have a huge effect on restraining cancer growth when KRAS is mutated. It is seen that mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, colon cancer and human lung cancer in particular.

Narayana Yeddula, first author of the paper and a Salk research associate opined that since activating EphA2 led to the suppression of both cell signaling and cell proliferation, this enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma.

The Salk researchers used data from the Cancer Genome Atlas data – a 10-year national project that mapped the genomes of hundreds of patients for over 20 different cancers. The data thus analysed lead to the discovery that genetic alterations of EphA2 were detected in 54 out of 230 patients with adenocarcinoma. It was also found by the team that the loss of EphA2 activated a pathway commonly associated with cancer that promotes tumor growth.

Yifeng Xia, a Salk staff researcher involved in the work remarked about another interesting aspect of the findings. He said that among human lung cancer patients with EphA2 mutations, around 8 percent of patients actually have high EphA2 expression. So, there are cases when EphA2 is not suppressing tumors and is likely to be context-dependent. Hence, for designing new therapeutics there is a need to carefully evaluate the molecule and its functions.

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