RAF proteins help regulate cell growth and survival in mammals, and mutations to RAF proteins cause a large number of cancers. The V600E mutation of BRAF (BRAFV600E) is one of three RAF variants. It’s found in nearly half of melanoma tumors, about 40 percent of thyroid cancers, and 10 percent of colorectal cancers. Melanoma tumors with BRAFV600E respond well to treatment with RAF inhibitors but eventually become resistant to the therapy; thyroid and colorectal cancers with BRAFV600E are largely resistant to RAF inhibitor treatment. Studies suggest that resistance to the inhibitors occurs when two molecules of the BRAFV600E protein combine to form a specific structure called a dimer.

Evripidis Gavathiotis, Ph.D., has been awarded a five-year, $2.1 million National Institutes of Health grant to design a new class of BRAF inhibitors that specifically target BRAFV600E dimers.

His lab recently discovered that ponatinib, an FDA-approved drug for treating certain leukemias, specifically recognizes BRAFV600E dimers in melanoma. He and his colleagues created a ponatinib-hybrid compound that will provide the foundation for the new RAF inhibitors they hope to develop. Dr. Gavathiotis is professor of biochemistry and of medicine. (R01CA238229)