BRAF inhibitors (e.g.,
vemurafenib) are widely used to treat metastatic
melanoma with the BRAF V600E
mutation. The initial response is often dramatic, but
treatment resistance leads to
disease progression in the majority of cases. Although
secondary mutations in the
mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of
patients. Here we
report a
genome- and
transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A
microfluidic chip with a concentration gradient of
vemurafenib was utilized to rapidly obtain
therapy-resistant
clones from two
melanoma cell lines with the BRAF V600E
mutation (A375 and SK-MEL-28).
Exome and
transcriptome data were produced from 13 resistant
clones and analyzed to identify
secondary mutations and
gene expression changes. Various mechanisms, including
phenotype switching and
metabolic reprogramming, have been determined to contribute to resistance development differently for each
clone. The
roles of
microphthalmia-associated transcription factor, the master
transcription factor in
melanocyte differentiation/dedifferentiation, were highlighted in terms of
phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor
therapy.