ABSTRACT
Latest whole-genome sequencing in 5 cancer patients confirms the highly heterogeneity and complexity of cancer. Not only multiple driver mutations in many cancer genes are implicated but also their sophisticated interactions complicate cancer treatment prove the limitations of currently used single gene-based targeted agents.
Cell proliferation, survival and apoptosis are regulated by signalling pathways, which transfer signals from cell surface (receptors) to the nucleus. In cancer, mutations accumulating in key components (genes) of these pathways deregulate signal transduction and cellular processes (proliferation, survival, apoptosis). Current evidence suggests that ~60 to 100 genetic alterations deregulate ~8 to 12 signalling pathways (EGFR, VEGF, Wnt/Notch, Hedgehog and others) for each individual cancer. Moreover, the interconnections (interactions) between these pathways with protein-protein interactions, synthesize a highly complex signalling pathways network. Therefore, the probability of clinical success with the current generation or in clinical development drugs targeting single components of pathways, given the sophisticated pathways network, is minimal.
In this review article, I describe the necessity, the challenges, and the perspectives of next-generation, network-based development of biomarkers and targets. Two are the major future goals: First, the completion of the catalogue of mutations and genes implicated in various cancer types. Second, the understanding of the functional role of protein-coding genes and their interactions in signalling pathways network. Because the genetic catalogue completion will require several decades for complete cancer-genome sequencing of thousands of patients for each cancer type and tumor stage, an alternative reverse engineering approach is provided. This network modelling integrating both clinical and genetic data available for some cancers may faster lead to biomarkers and biologics development for network-based personalized cancer medicine.
Editor's choice : This extensive review article (23 pages) includes 1 box, 1 table and 4 figures which summarize a current landscape of systems biology and oncology.
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