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.
Highlights
Melanoma is one of the most aggressive malignancies with a high mutational burden [1]
MAP2K1/2, termed mitogen-activated extracellular signal-regulated kinases 1/2 (MEK1/2), which activate extracellular signal-regulated kinases 1/2 (ERK1/2) [7,8,18]. Targeting approaches addressing this pathway using sorafenib were not successful, but recently developed more specific BRAF inhibitors led to high response rates, leading to a median overall survival of 24 months when combined with MEK1/2 inhibitors and response rates of up to 65%
Combination treatment with MEK1/2 inhibitors reduces side-effects that have associated with mutated up- or downstream molecules which act as tumor suppressors, e.g., cyclinbeen linked to paradoxical mitogen-activated protein kinase (MAPK) pathway activation via CRAF by BRAF inhibitors in normal cells dependent kinase inhibitor 2A (CDKN2A) (p16, p14ARF), TP53, and phosphatase and tensin carrying the wildtype BRAF allele [19]
Summary
Melanoma is one of the most aggressive malignancies with a high mutational burden [1]. While anti-CTLA-4 antibody treatment leads to immune activation in central lymphoid organs, anti-PD-1 or anti-PD-1L antibodies reactivate (normalize) peripheral tumor immunity in the tissue microenvironment [15] This knowledge has led to a new immune-based therapeutic approach using monoclonal antibodies directed against CTLA-4 and PD-1/PD-L1, which have been approved for a variety of different cancers such as melanoma, lung cancer, head and neck cancer, and renal cell carcinoma, with ongoing research to find new immune targets [16]. Despite using either targeted treatment or immune-based therapies, recurrence rates are still high and affect the vast majority of patients This may in part be due to the fact that the complex interplay between different pathways, reactivation of transcriptomic patterns and tumor heterogeneity are poorly understood up to now. Principles of Mitogen-Activated Protein Kinase (MAPK) and Cellular Homolog of v-Kit
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