Uveal Melanoma (UM) is a fatal cancer of the colored cells in the eye. It is the most common type of eye cancer, with ~1500 new patients per year diagnosed with the disease. In contrast to most cancers, which can originate from many different DNA mutations, >80% of UM patients have the same mutation in a protein called G alpha Q (Gq). Gq is a signaling protein involved in the normal functioning of the heart, nervous system, and blood clotting cascade and thus it is unlikely this protein will be targeted with a drug itself.
We are interested in a protein which Gq interacts with, called Trio, as an alternate way to reduce the cancerous effects of mutant Gq. When our collaborators reduce the levels of Trio experimentally, the size of UM tumors grown in the lab decrease in size and volume significantly, indicating that targeting Trio with a drug might be a good option for uveal melanoma patients.
However, the pathway to targeting Trio with a drug is not straightforward as we do not understand very much about this protein. Trio is an extremely large protein whose structure is mostly unknown.
To get at this problem, researchers at the University of Michigan, Purdue University, and the University of California San Diego have defined how a very important piece of Trio is regulated, through work outlined in a publication in Science Signaling.
Principally using a technique called X-ray Crystallography, which allows researchers to visualize individual protein molecules that are too small to be seen by the human eye, these researchers have discovered what Trio looks like. They’ve shown that Trio exists in a state which is trapped, acting as a dam for cancerous signals until it meets the mutant Gq. Mutant Gq breaks this dam open and allows for the full flow of cancerous signals, leading to the growth and spread of tumors.
Another important finding of the study is that mutations in Trio itself can break the dam of signaling open, and this team has identified mutations in Trio from cancer patients which do lead to hyperactive signaling.
Researchers hope to identify drugs that can stabilize the trapped state of Trio and thus provide a possible mechanism for treating uveal melanoma. This is more feasible than targeting Gq, as Trio does not play as many roles in adult humans. The Tesmer Lab is currently involved in drug screening against Trio using two different strategies, and the Gutkind lab is searching for proteins “down the signaling stream” from Trio that could serve as surrogate targets for Uveal Melanoma.
These findings are described in the article entitled Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential, recently published in the journal Science Signaling.