5 10.2217/FON.12.169 © 2013 Future Medicine Ltd ISSN 1479-6694 Future Oncol. (2013) 9(1), 5–8 Future Oncology part of Identifying and targeting driver somatic mutations and deregulated signaling pathways of cancer cells has proved an effective therapeutic concept in oncology, but resistance in clinical practice remains challenging. In malignant melanoma, V600 mutation in BRAF is very common and several drugs inhibiting the RAF– MEK–MAPK downstream pathway, one of two main signaling transduction axes of EGFR, have been developed. The progress is very fast with monotherapy with vemurafenib, dabrafenib or trametinib, each acting as BRAF and MEK inhibitors to improve progression-free survival with or without overall survival in patients with metastatic melanoma whose tumor cells harbor BRAF V600 mutations. In an effort to prolong further survival, the combined treatment with dabrafenib and trametinib is now evaluated. Perspectives and challenges of this combined regimen, along with clinical applications of high- throughput (HT) next-generation sequencing (NGS) technologies and microarray platforms for next-generation biomarkers and drugs, are discussed. Targeted treatment Deregulation of biochemical signaling pathways occurs through a variety of molecular mechanisms including driver mutations, epigenetic aberrations, transcriptional activity, dysfunction of biological networks and perhaps other processes. Common complex chronic diseases arise from the accumu- lation of these events. Deregulation of pathways involved in cell proliferation, growth, survival, apoptosis, angiogenesis, metabolism, invasion and metastasis are considered the hallmarks of cancer [1]. Changes in the evaluation of gene expression patterns, function and regulation, and of proteins have a crucial role in intracellular signaling transduction, disease pathogenesis and cancer progress. Modern biotechnology research, pharmaceutical industry and academia is focused on the exploration of genes, proteins and signaling pathways involved in healthy and diseased states, aiming at providing more robust diagnostics and biomarkers and more effective drugs. Gene expression regulation and signaling pathway-based inhibitors represent the fundamental concept of targeted therapy attracting the major interest of the pharmaceutical industry for identifying key targets for cancer and developing novel drugs. One of several signaling pathways involved in cancer is the RAF–MEK– ERK pathway, which is activated through RAS oncoproteins or mutations in these genes, and at present in approximately 20% of cancers [2] . In malignant melanomas, activating V600E mutations in BRAF have been found in 66%, and these BRAF mutations have also been detected (but at a lower frequency) in other cancer types [2] . Until recently, dacarbazine, a chemotherapeutic drug, was the only available drug approved by the US FDA for the treatment of metastatic melanoma. However, the response rate was modest and did not balance the adverse events of this cytotoxic agent. The advent of vemurafenib (PLX4032), a BRAF inhibitor, has changed the treatment of the disease. In a Phase III randomized trial, vemurafenib, as compared with dacarbazine, improved response rate, progression-free survival and overall survival in patients with metastatic melanoma and the BRAF V600E mutation [3] . Dabrafenib, another inhibitor of mutated BRAF, significantly prolonged time to progression in patients with BRAF V600E mutant metastatic melanoma [4] . From targeted monotherapy to combined BRAF–MEK inhibitors and integrated genome analysis for melanoma treatment “ Although evidence supports the efficacy of a combination regimen of BRAF–MEK complex of inhibitors in advanced melanoma, no convincing data on overall survival benefit are provided... ” Dimitrios H Roukos* 1 , Costas Papaloukas 1,2 & Margaret Tzaphlidou 1,3 1 Centre for Biosystems & Genomic Network Medicine, Ioannina University, 45110 Ioannina, Greece 2 Department of Biological Applications & Technology, University of Ioannina, Greece 3 Department of Medical Physics, Ioannina University, Ioannina, Greece *Author for correspondence: Tel.: +30 2651007423 n droukos@uoi.gr Editorial Keywords n BRAF mutations n combined targeted treatment n genome analysis n MEK inhibitors n melanoma n resistance For reprint orders, please contact: reprints@futuremedicine.com