Splicing out BRAF's resistance

U.S. researchers have uncovered a mechanism by which melanomas expressing mutant BRAF acquire resistance to targeted drugs.¹ The findings represent the first time a splice variant has been implicated in cancer drug resistance. The findings give companies a new resistance mechanism to screen against in the design of next-generation BRAF inhibitors and also further the case for combining Zelboraf with downstream kinase inhibitors.

BRAF is part of the Ras/Raf/MEK/MAPK signaling cascade, which is collectively known as the MAPK pathway. Activating mutations in BRAF-which result in tumor dependency on the MAPK signaling cascade-are found in about half of melanoma cases. The V600E mutation is by far the most predominant and occurs in about 90% of melanomas driven by mutant BRAF.²...