In the first study, 21 patients with melanoma were treated with the RAF inhibitors dabrafenib or vemurafenib and 9 patients were treated with dabrafenib plus the MEK inhibitor trametinib (Carlino et al., 2013; Long et al., 2014). Biopsies were obtained prior to treatment and at the time of relapse, and on-treatment biopsies were taken in four patients. The authors performed expression profiling on the Illumina beadchip platform (GSE50509, GSE61992). Comparing four on-treatment biopsies to the pre-treatment biopsies, we observed strong positive connectivity to multiple signatures of MAP kinase inhibition, consistent with drug-induced silencing of the MAP kinase pathway. Analysis at the time of relapse showed that several patients showed strong negative connectivity to these same CMap perturbations, suggestive of reactivation of the MAP kinase pathway – a known mechanism of drug resistance in melanoma (Wagle et al., 2014). One of those patients (patient 10) had a MAP kinase-activating BRAF splice variant, consistent with the CMap results (Figure 7B). Pathway reactivation was also detected in a resistant tumor with MAP2K1 mutation (patient C1) and in a resistant tumor with BRAF amplification (patient C10).
