Figure II. Controlling protein-protein interaction networks in cancer via epichaperomes.

PPI network plasticity in cancer, which arises from highly redundant signaling pathways, poses a challenge to therapy and accounts for treatment resistance. Pharmacologically rewiring PPI networks into a hyperconnected state can be a modality for inducing therapeutic vulnerability. Existing treatments may be more effective than previously observed if PPI network hyperconnectivity, whereby cancerous cells are forced into a state devoid of redundancy, is created prior to drug treatment. Several inhibitors and degraders of PPI network nodes are already in clinical use or in development, making this approach both timely and potentially transformative. This treatment paradigm is not a combination method per se because the hyperconnectivity inducer is used once to prime the tumor, followed by current therapy. This approach also differs from synthetic lethality where simultaneous perturbation of two or more genes is required for cell death. Figure adapted from ref. [33].