Modelling of protein kinase signaling pathways in melanoma and other cancers

Abstract

Melanoma is a highly aggressive tumor with a strong dependence on intracellular signaling pathways. Almost half of all melanomas are driven by mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) with BRAFV600E being the most prevalent mutation. Recently developed targeted treatment directed against mutant BRAF and downstream mitogen-activated protein kinase (MAPK) MAP2K1 (also termed MEK1) have improved overall survival of melanoma patients. However, the MAPK signaling pathway is far more complex than a single chain of consecutively activated MAPK enzymes and it contains nested-, inherent feedback mechanisms, crosstalk with other signaling pathways, epigenetic regulatory mechanisms, and interacting small non-coding RNAs. A more complete understanding of this pathway is needed to better understand melanoma development and mechanisms of treatment resistance. Network reconstruction, analysis, and modelling under the systems biology paradigm have been used recently in different malignant tumors including melanoma to analyze and integrate ‘omics’ data, formulate mechanistic hypotheses on tumorigenesis, assess and personalize anticancer therapy, and propose new drug targets. Here we review the current knowledge of network modelling approaches in cancer with a special emphasis on melanoma.