Other Paths to Resistance Illuminated: Epigenetic and Transcriptional Adaptations

Much of the inquiry into BRAF/MEK-inhibitor resistance focuses on new mutations or genomic alterations. These are reproducibly important, but epigenetic and transcriptional changes that drive adaptation to inhibitor therapy remain understudied. Hugo and colleagues address this gap, analyzing paired melanoma tumor samples pretreatment and at progression following either BRAF inhibitor (BRAFi) or combined BRAFi/MEKi therapy.

In 67 pairs, major mutational drivers of resistance included activating mutations in KRAS, NRAS, BRAF, and MEK1. Most interesting were transcriptional changes analyzed in 48 sets of matched samples, which included increased expression of NRAS, KRAS, and BRAF. Growth factor signaling receptors, notably c-MET and EPHA2, were…