Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

Certain members of the Ras superfamily of small GTPases are commonly deregulated in human cancers, but how can we target them? This Review explores the association of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate GTPases with cancer and discusses whether they can be effectively targeted therapeutically. There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP–GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.