Some of the most infamous drivers of cancer are mutations in RAS genes, which lead to tumor growth in about a quarter of all cancer patients. Scientists at the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute have determined the molecular structure of a RAS-pathway protein called SHOC2 and two other proteins it binds to. This three-protein assembly, called the SHOC2-MRAS-PP1C (“SMP”) complex, regulates the RAS signaling pathway and helps cancer cells with RAS mutations survive.
The high-resolution structure of this complex, revealed through X-ray crystallography and cryogenic electron microscopy, suggests possible ways that drugs can bind to it to inhibit the RAS pathway and block cancer growth. The study, published in Nature, highlights a potential therapeutic strategy for a signaling pathway that has been difficult to target with drugs. The work is the result of a collaboration between researchers at Dana-Farber, Deerfield Discovery and Development, a subsidiary of Deerfield Management Company, and in the Broad’s Cancer Program, Genetic Perturbation Platform, and the Center for the Development of Therapeutics (CDoT).
“By solving the structure, we’ve learned a lot about how SHOC2 operates in this circuit, which points out ways in which you can therapeutically intervene,” said study co-senior author and Broad institute member William Hahn of the Cancer Program. Hahn is also the William Rosenberg Professor of Medicine, executive vice president and the chief operating officer at Dana-Farber.
