Diffuse gastric cancer (DGC) is characterized by frequent missense mutations in the small GTPase RHOA, but the effects of this mutation on enzyme activity and signaling have been widely debated. In this issue, Zhang and colleagues show that the most common RHOA mutation in DGC, encoding RHOAY42C, represents a gain of function; that a mouse model incorporating this mutation in association with loss of the E-cadherin gene CDH1 recapitulates many aspects of DGC; and that rationally designed therapeutics based on our understanding of RHOA signaling are promising agents for treating DGC.See related article by Zhang et al., p. 288.
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