RAS GTPase signalling to alternative effector pathways

Abstract

RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS signalling is highly complex, and in addition to RAF and PI3K these small GTPase proteins can interact with an array of alternative effectors that feature RAS binding domains. The consequence of RAS binding to these effectors remains relatively unexplored, but these pathways may provide targets for combinatorial therapeutics. We discuss here three candidate alternative effectors: RALGEFs, RASSF5 and AFDN, detailing their interaction with RAS GTPases and their biological significance. The metastatic nature of RAS-driven cancers suggests more attention should be granted to these alternate pathways, as they are highly implicated in the regulation of cell adhesion, polarity, cell size and cytoskeletal architecture.