Pathway drug cocktail: targeting Ras signaling based on structural pathways

TL;DR

This paper proposes a structural pathway-based approach to designing drug cocktails targeting Ras signaling, aiming to improve treatment of Ras-mutant tumors by integrating structural, functional, and clinical data.

Contribution

It introduces a novel framework for classifying pathway combinations using structural network knowledge to develop effective drug cocktails for Ras-driven cancers.

Findings

Structural network integration aids in identifying effective drug combinations.

Pathway drug cocktails can target multiple tumorigenic processes.

The approach can be extended to other signaling proteins.

Abstract

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.