Decoding the functional impact of the cancer genome through protein-protein interactions

Acquisition of genomic mutations enables cancer cells to gain fitness advantages under selective pressure and, ultimately, leads to oncogenic transformation. Interestingly, driver mutations, even within the same gene, can yield distinct phenotypes and clinical outcomes, necessitating a mutation-focused approach. Conversely, cellular functions are governed by molecular machines and signalling networks that are mostly controlled by protein-protein interactions (PPIs). The functional impact of individual genomic alterations could be transmitted through regulated nodes and hubs of PPIs. Oncogenic mutations may lead to modified residues of proteins, enabling interactions with other proteins that the wild-type protein does not typically interact with, or preventing interactions with proteins that the wild-type protein usually interacts with. This can result in the rewiring of molecular signalling cascades and the acquisition of an oncogenic phenotype. Here, we review the altered PPIs driven by oncogenic mutations, discuss technologies for monitoring PPIs and provide a functional analysis of mutation-directed PPIs. These driver mutation-enabled PPIs and mutation-perturbed PPIs present a new paradigm for the development of tumour-specific therapeutics. The intersection of cancer variants and altered PPI interfaces represents a new frontier for understanding oncogenic rewiring and developing tumour-selective therapeutic strategies.