‘Pathway drug cocktail’: targeting Ras signaling based on structural pathways

• Approximately 20% of all human cancers have oncogenic mutations in the RAS gene.
• Therapeutic approaches based on the inhibition of Ras-mediated signaling have been challenging.
• ‘Pathway drug cocktails’ combinations aiming at parallel pathways appear promising.

Tumors bearing Ras mutations are notoriously difficult to treat. Drug combinations targeting the Ras protein or its pathway have also not met with success. ‘Pathway drug cocktails’, which are combinations aiming at parallel pathways, appear more promising; however, to be usefully exploited, a repertoire of classified pathway combinations is desirable. This challenge would be facilitated by the availability of the structural network of signaling pathways. When integrated with functional and systems level clinical data, they can be powerful in advancing novel therapeutic platforms. Based on structural knowledge, drug cocktails may tear into multiple cellular processes that drive tumorigenesis, and help in deciphering the interrelationship between Ras mutations and the rewired Ras network. The pathway drug cocktail paradigm can be applied to other signaling protein targets.