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PRIMES: Protein interaction machines in oncogenic EGF receptor signalling

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Protein interactions and signalling in cancer

Neoplastic transformation is usually associated with mutations, epigenetic changes and altered gene expression. Understanding the impact of these changes in the physiological protein interaction network is central for the design of novel therapies against cancer.

Fundamental Research

The epidermal growth factor receptor (EGFR/ErbB) network constitutes one of the most important signalling pathways as it regulates key developmental processes including cell proliferation and differentiation. Various oncogenic perturbations hijack the EGFR pathway, altering the proteins interaction landscape, and hence, the final cellular response. Given its implication in cancer development, there is a great interest to understand the molecular details underlying EGFR signalling. The EU-funded PRIMES project investigated the molecular signal processing functions of the EGFR network and how it rewires in pathogenic conditions such as colorectal cancer and breast cancer. The consortium worked under the hypothesis that signal transduction networks are essentially protein interaction networks, which undergo dynamic changes to signal information within cells. PRIMES used a combination of proteomics, imaging, structural biology, computational and mathematical modelling and went beyond classical mapping, which gives a static snapshot of possible protein to protein interactions. The consortium used fluorescence lifetime imaging microscopy to assess protein interaction dynamics and protein concentrations in real time. In addition, molecular mechanistic details were generated by determining the structure of selected interaction partners. Network and pathway analysis were employed alongside mathematical modelling to reconstruct signalling network topologies and understand how proteins interact under different situations. From a therapeutic perspective, using a combination of in silico and in vitro approaches, PRIMES partners identified chemical compounds that target specific protein interactions. The compounds were evaluated in cell culture assays as well as in colorectal cancer mouse models with promising results. The PRIMES study provided unprecedented evidence that protein complexes serve as molecular signal processing machines, and highlighted new opportunities for interfering with these networks for therapeutic purposes. Researchers envision targeting protein to protein interactions to avoid or overcome resistance to currently used signal transduction inhibitors.


Protein interactions, cancer, EGFR, signaling, PRIMES

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