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WIREs Syst Biol Med
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Developing melanoma therapeutics: overview and update

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Abstract Melanoma is a common, often deadly malignancy, historically associated with limited treatment options for advanced disease. In recent years, systems‐based research has resulted in significant clinical advancements. Strategic inhibition of mutated oncoproteins and targeting of immune checkpoints have emerged as very promising approaches. Vemurafenib, which received US Food and Drug Administration (FDA) approval in 2011, selectively inhibits BRAFV600E, a hyperactivated mutant signaling kinase in the mitogen‐activated protein kinase (MAPK) pathway. Another recently FDA‐approved drug, ipilimumab, blocks the cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) pathway from inhibiting T cell activation. Despite this apparent progress, compelling challenges remain for both researchers and clinicians. Responses to therapy remain unacceptably incomplete and, in most cases, resistance mechanisms quickly develop that lead to relapse and subsequent patient mortality. Combining therapeutic modalities may increase the percentage of responding patients as well as the magnitude and durability of response. Notably, combined therapies involving selective BRAF inhibitors (SBIs) and other inhibitors of MAPK‐dependent or MAPK‐independent resistance pathways appear particularly promising. Preclinical and clinical studies are needed to comprehensively evaluate the optimal combinations of therapies, to identify melanoma subtypes that will be most responsive, and to determine optimal dosing, timing, and route of delivery. WIREs Syst Biol Med 2013, 5:257–271. doi: 10.1002/wsbm.1210 This article is categorized under: Translational, Genomic, and Systems Medicine > Therapeutic Methods

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Overview of the MAPK pathway and selected inhibitors. The MAPK pathway has emerged as one of the most promising targets of oncogenic driver inhibition. Small‐molecule inhibitors, vemurafenib and dabrafenib, selectively block BRAFV600E while trametinib and selumetinib selectively inhibit MEK1/2.

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Overview of immunotherapeutic approaches. Fully humanized anti‐CTLA‐4 antibodies, ipilimumab and tremelimumab, block binding of CD80 or CD86 with CTLA‐4 and thus prevent signaling that inhibits T cell activation. BMS‐936558 and BMS‐936559 represent fully humanized anti‐PD‐1 and PD‐L1 antibodies, respectively, which act on the PD‐1 pathway to prevent inhibitory T cell signaling.

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