November 12, 2020

New therapeutic target for lung cancer

Vanderbilt researchers have identified a new molecular partner — and potential therapeutic target — in a signaling axis that drives lung cancer.

Continuous activation of cell surface receptors increases signaling that can promote oncogenic transformation. One receptor, EphA2, has been identified as a driver of lung cancer, but its interacting partners are not well characterized. 

Reporting in Molecular Cancer ResearchJin Chen, MD, PhD, Dana Brantley-Sieders, PhD, and colleagues have identified a novel interactor of EphA2 that promotes growth of non-small cell lung cancer.   

Using a yeast-two-hybrid screen where EphA2 acts as a bait protein and a library of potential interactors from lung cancer cells acts as prey, the researchers found that the enzyme PLCgamma1 strongly interacts with EphA2.  

In human lung cancer cells, genetic or pharmacologic inhibition of EphA2 kinase activity decreased the phosphorylation (activation) of PLCgamma1 and the loss of PLCgamma1 inhibited tumor cell growth in vitro. Knockout of PLCgamma1 by CRISPR-mediated genome editing also impaired tumor growth in a mouse lung cancer model. 

The EphA2-PLCgamma1 signaling axis thus is a potential therapeutic target for the treatment of EphA2-driven lung cancers.

National Institutes of Health grants CA177681, CA095004, CA009592 and CA220804 and the Department of Veterans Affairs supported the research