Response to targeted therapies varies significantly despite shared oncogenic mutations.,Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace.,Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized.,Here, we found that EGFR induced vemurafenib resistance is ligand dependent.,We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling.,An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients’ tumor specimens.,Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype.,In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors.,These findings indicate that an “autocrine drug resistance loop” is suppressed by melanocyte lineage signal(s), such as MITF.,This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.
We characterized the mutational landscape of human skin cutaneous melanoma (SKCM) using data obtained from The Cancer Genome Atlas (TCGA) project.,We analyzed next-generation sequencing data of somatic copy number alterations and somatic mutations in 303 metastatic melanomas.,We were able to confirm preeminent drivers of melanoma as well as identify new melanoma genes.,The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients.,The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts.,A multi-step filter enriched somatic mutations while accounting for recurrence, conservation, and basal rate.,Thus, this filter can serve as a paradigm for analysis of genome-wide next-generation sequencing data of large cohorts with a high mutational burden.,Analysis of TCGA melanoma data using such a multi-step filter discovered novel and statistically significant potential melanoma driver genes.,In the context of the Pan-Cancer study we report a detailed analysis of the mutational landscape of BRAF and other drivers across cancer tissues.,Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level.