Now showing 1 - 4 of 4
  • Publication
    The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells
    The intricate dynamic control and plasticity of RAS to ERK mitogenic, survival and apoptotic signalling has mystified researches for more than 30 years. Therapeutics targeting the oncogenic aberrations within this pathway often yield unsatisfactory, even undesired results, as in the case of paradoxical ERK activation in response to RAF inhibition. A direct approach of inhibiting single oncogenic proteins misses the dynamic network context governing the network signal processing. In this review, we discuss the signalling behaviour of RAS and RAF proteins in normal and in cancer cells, and the emerging systems-level properties of the RAS-to-ERK signalling network. We argue that to understand the dynamic complexities of this control system, mathematical models including mechanistic detail are required. Looking into the future, these dynamic models will build the foundation upon which more effective, rational approaches to cancer therapy will be developed.
    Scopus© Citations 54  663
  • Publication
    An Integrative Computational Approach for a Prioritization of Key Transcription Regulators Associated With Nanomaterial-Induced Toxicity
    A rapid increase of new nanomaterial products poses new challenges for their risk assessment. Current traditional methods for estimating potential adverse health effect of nanomaterials (NMs) are complex, time consuming and expensive. In order to develop new prediction tests for nanotoxicity evaluation, a systems biology approach and data from high-throughput omics experiments can be used. We present a computational approach that combines reverse engineering techniques, network analysis and pathway enrichment analysis for inferring the transcriptional regulation landscape and its functional interpretation. To illustrate this approach, we used published transcriptomic data derived from mice lung tissue exposed to carbon nanotubes (NM-401 and NRCWE-26). Because fibrosis is the most common adverse effect of these NMs, we included in our analysis the data for bleomycin (BLM) treatment, which is a well-known fibrosis inducer. We inferred gene regulatory networks for each NM and BLM to capture functional hierarchical regulatory structures between genes and their regulators. Despite the different nature of the lung injury caused by nanoparticles and BLM, we identified several conserved core regulators for all agents. We reason that these regulators can be considered as early predictors of toxic responses after NMs exposure. This integrative approach, which refines traditional methods of transcriptomic analysis, can be useful for prioritization of potential core regulators and generation of new hypothesis about mechanisms of nanoparticles toxicity.
    Scopus© Citations 7  555
  • Publication
    Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
    Clinically used RAF inhibitors are ineffective in RAS-mutant tumors because they enhance homo- and heterodimerization of RAF kinases, leading to paradoxical activation of ERK signaling. Overcoming enhanced RAF dimerization and the resulting resistance is a challenge for drug design. Combining multiple inhibitors could be more effective, but it is unclear how the best combinations can be chosen. We built a next-generation mechanistic dynamic model to analyze combinations of structurally different RAF inhibitors, which can efficiently suppress MEK/ERK signaling. This rule-based model of the RAS/ERK pathway integrates thermodynamics and kinetics of drug-protein interactions, structural elements, post-translational modifications and cell mutational status as model rules to predict RAF inhibitor combinations for inhibiting ERK activity in oncogenic RAS and/or BRAFV600E backgrounds. Predicted synergistic inhibition of ERK signaling was corroborated by experiments in mutant NRAS, HRAS and BRAFV600E cells, and inhibition of oncogenic RAS signaling was associated with reduced cell proliferation and colony formation.
    Scopus© Citations 43  357
  • Publication
    Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS G13D
    Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
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