Protocol to discover actionable cancer vulnerabilities enabled by neomorph protein-protein interactions with the AVERON Notebook

While some tumor driver mutations inhibit existing protein-protein interactions (PPIs), others can create neomorph interactions (neoPPIs) not characteristic of the wild-type counterparts. Such tumor-specific neoPPIs may represent targets for therapeutic interventions. Here, we present a protocol to computationally uncover neoPPI-enabled druggable tumor dependencies using the AVERON Notebook environment. We describe steps for determining PPI levels, identifying clinically significant neoPPIs, and determining neoPPI-regulated pathways. We then detail procedures for determining neoPPI-regulated therapeutically actionable targets. For complete details on the use and execution of this protocol, please refer to Chen et al.¹.