Mapping oncogenic protein interactions for precision medicine

Normal protein-protein interactions (normPPIs) occur with high fidelity to regulate almost every physiological process. In cancer, this highly organised and precisely regulated network is disrupted, hijacked or reprogrammed resulting in oncogenic protein-protein interactions (oncoPPIs). OncoPPIs, which can result from genomic alterations, are a hallmark of many types of cancers. Recent technological advances in the field of mass spectrometry (MS)-based interactomics, structural biology and drug discovery have prompted scientists to identify and characterise oncoPPIs. Disruption of oncoPPI interfaces has become a major focus of drug discovery programs and has resulted in the use of PPI-specific drugs clinically. However, due to several technical hurdles, studies to build a reference oncoPPI map for various cancer types have not been undertaken. Therefore, there is an urgent need for experimental workflows to overcome the existing challenges in studying oncoPPIs in various cancers and to build comprehensive reference maps. Here, we discuss the important hurdles for characterising oncoPPIs and propose a three-phase multidisciplinary workflow to identify and characterise oncoPPIs. Systematic identification of cancer-type-specific oncogenic interactions will spur new opportunities for PPI-focused drug discovery projects and precision medicine.

Automated summary

Normal protein-protein interactions (normPPIs) play a crucial role in regulating physiological processes, but in cancer, this organized network is disrupted, leading to oncogenic protein-protein interactions (oncoPPIs). Recent advancements in mass spectrometry (MS), structural biology, and drug discovery have allowed scientists to identify and characterize oncoPPIs. However, the construction of a reference oncoPPI map for different types of cancers is still lacking due to technical challenges. Therefore, there is an urgent need to develop experimental workflows to overcome these challenges and create comprehensive reference maps.