New players in melanoma
Although mutant BRAF dominates any discussion about melanoma targets, activating mutations in the kinase occur only in 50% of patients, implying that other factors are at work. Researchers at Children's Hospital Boston and colleagues have used zebrafish models to identify two such factors: DHODH, an enzyme already being targeted for autoimmune diseases, and a histone methyltransferase called SETDB1.1,2
In one Nature paper, the team reported that inhibitors of dihydroorotate dehydrogenase (DHODH) increased therapeutic responses in melanoma cells and mouse models in combination with PLX4720, a small molecule inhibitor of the oncogenic BRAF V600E mutation from Plexxikon Inc. PLX4032, a related BRAF inhibitor with better pharmacokinetics from Plexxikon and Roche, is in Phase III testing for melanoma.
A second Nature paper from the same group identified SET domain bifurcated 1 (SETDB1) as a melanoma oncogene that is overexpressed in the majority of melanomas and causes the disease to