Community Research and Development Information Service - CORDIS

FP7

PRIMES — Result In Brief

Project ID: 278568
Funded under: FP7-HEALTH
Country: Ireland

Protein interactions and signalling in cancer

Deconstructing the molecular interactions in cancer cells could lead to the discovery of novel drug targets. A European study of the dynamic interactions among proteins in oncogenic signalling.
Protein interactions and signalling in cancer
Protein interactions play a key role coordinating cellular responses. The epidermal growth factor receptor (EGFR/ErbB) signalling network regulates cell proliferation and differentiation. Aberrant EGFR signalling is encountered in many cancers, suggesting that it may play a central role in disease onset or progression.

The EU-funded PRIMES (PRIMES: Protein interaction machines in oncogenic EGF receptor signalling) project uncovers the role of EGFR signalling in colorectal cancer (CRC) and breast cancer. Researchers are employing a combination of fluorescence imaging, structural biology, protein engineering, proteomics and mathematical modelling to analyse protein interactions within the EGFR pathway and elucidate their role. Understanding functional pathogenesis of CRC will enable the research scientists to identify mechanisms of drug resistance and test drug efficacy.

PRIMES researchers are investigating protein interactions as targets, and are screening pharmacophore-rich allosteric chemical compound libraries and peptidomimetic libraries against protein interactions. In addition, they are using translational applications to overcome drug resistance in cancer, related to ERBBs. The focus is also on targeting protein interactions to avoid or overcome resistance to currently used signal transduction inhibitors.

Using 93 selected baits, the research finalised static maps of oncogenic and non-oncogenic interactomes (the whole set of molecular interactions in a particular cell). Twenty core ErbB network component proteins were analysed by western blotting. The work also produced and validated 184 antibodies specific to the protein nodes in the EGFR network. Novel mathematical methods were developed for classification of the temporal and spatial-temporal EGFR phosphorylation patterns. Analysis of the biochemical pathways even identified a novel player involved in EGFR degradation.

Analysis of the protein complexes as molecular signal processing machines transcended the traditional perception of the role of protein interactions. Applying this strategy to the cancer-related EGFR/ ErbB network enabled exploration of the emergent network properties arising from protein interactions. Deliverables will help design new, efficacious and targeted therapies to overcome the poor therapeutic responses and resistance observed with traditional drugs.

Related information

Subjects

Life Sciences

Keywords

Protein interactions, cancer, oncogenic, epidermal growth factor, drug resistance
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