Taming Oncogenic Signaling at Protein Interfaces: Challenges and Opportunities

Many key cellular events determining the thin line between healthy and oncogenic behavior rely on the proper functioning of protein-protein interactions (PPIs). Alterations that affect the affinity of a protein-protein binding site may destabilize a desired healthy interaction, or stabilize an oncogenic interaction. The understanding that there are a few key hot-spot residues that are mainly responsible for the binding energy of an interaction greatly widened the prospects of targeting oncogenic protein-protein interfaces enabling the use of small ligands in addition to biological molecules such as peptides and antibodies. Taming oncogenic signaling requires a deep understanding of protein interactions and their networks. Traditional representation of PPIs in signaling pathways as nodes and edges falls short of expressing interaction specific modulation of signals. Structural networks, deciphering which sites on a protein structure are responsible for each of the many interactions it may carry out, help understanding specific oncogenic mutations on signaling. We describe the key features of PPIs and their targeting, together with the advantages of structural networks, and provide four case studies demonstrating different opportunities for the aim of modulating oncogenic interactions.