Fig. 3.

Precision medicine profile and rational drug targeting of malignant melanoma. a Whole-slide tumor tissue image of malignant melanoma shows tumor microenvironment and its impact on metabolically and mitotically active melanoma cells. b Multiomics data of tumor specimen is matched with high-throughput functional genomics data of cellular cultures. The personalized precision medicine chart shows deregulation of important signaling and epigenetic molecules across matched data tracks of genomic, epigenomic, transcriptomic, proteomics, and metabolomics platforms. c Comparison of patient data with somatic copy number alterations (SCNAs) of melanoma cohort identifies significant amplifications (red) and d deletions (blue). Detected somatic alterations of BRAF and EZH2 coincide, fall into mutational hotspots, and result in gain-of-function oncogenes. The somatic landscape of ARID1A and ARID2 is characterized by somatic non-sense and missense mutations, which result in loss of function of a tumor suppressor complex involved in chromatin remodeling. e Rewiring of metabolism and metabolic signaling affects melanogenesis and tunes central carbon metabolism to support evasion, proliferation, and survival of malignant melanoma. f Oncometabolites impact the epigenetic machinery by blocking or supplying carbons for histone modifiers. Epigenetic master regulators in cancer control transcriptional activation of other oncogenes or repression of tumor suppressors. g Personalized medicine strategies to overcome treatment resistance of malignant melanoma patients. h Patient profiles of The Cancer Genome Altas (TCGA) reveal co-occurrence of BRAF and EZH2 hyperactivity making combination therapy of mitogen-activated kinase inhibitors (MAPKi) and epigenetic inhibitors (EPIi) viable. As alternative option if immunotherapy (IMMUNOi) fails due to immune evasion and suppression of immune receptors, combination therapy of IMMUNOi and metabolic inhibitors (METABi) is sensible