Kinase inhibition in the mitogen activated protein kinase (MAPK)                         pathway is a standard therapy for cancer patients with activating BRAF                         mutations.,However, the anti-tumorigenic effect and clinical benefit are                         only transient, and tumors are prone to treatment resistance and relapse.,To                         elucidate mechanistic insights into drug resistance, we have established an                         in vitro cellular model of MAPK inhibitor resistance in malignant                         melanoma.,The cellular model evolved in response to clinical dosage of the                         BRAF inhibitor, vemurafenib, PLX4032.,We conducted transcriptomic expression                         profiling using RNA-Seq and RT-qPCR arrays.,Pathways of melanogenesis, MAPK                         signaling, cell cycle, and metabolism were significantly enriched among the                         set of differentially expressed genes of vemurafenib-resistant cells vs                         control.,The underlying mechanism of treatment resistance and pathway                         rewiring was uncovered to be based on non-genomic adaptation and validated                         in two distinct melanoma models, SK-MEL-28 and A375.,Both cell lines have                         activating BRAF mutations and display metastatic potential.,Downregulation of dual specific phosphatases, tumor suppressors,                         and negative MAPK regulators reengages mitogenic signaling.,Upregulation of                         growth factors, cytokines, and cognate receptors triggers signaling pathways                         circumventing BRAF blockage.,Further, changes in amino acid and one-carbon                         metabolism support cellular proliferation despite MAPK inhibitor treatment.,In addition, treatment-resistant cells upregulate pigmentation and                         melanogenesis, pathways which partially overlap with MAPK signaling.,Upstream regulator analysis discovered significant perturbation in oncogenic                         forkhead box and hypoxia inducible factor family transcription factors.,The established cellular models offer mechanistic insight into                         cellular changes and therapeutic targets under inhibitor resistance in                         malignant melanoma.,At a systems biology level, the MAPK pathway undergoes                         major rewiring while acquiring inhibitor resistance.,The outcome of this                         transcriptional plasticity is selection for a set of transcriptional master                         regulators, which circumvent upstream targeted kinases and provide                         alternative routes of mitogenic activation.,A fine-woven network of                         redundant signals maintains similar effector genes allowing for tumor cell                         survival and malignant progression in therapy-resistant cancer.,The online version of this article (10.1186/s12918-018-0554-1) contains                         supplementary material, which is available to authorized users.
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.