Targeting the α4-α5 dimerization interface of K-RAS inhibits tumor formation in vivo

RAS genes are the most commonly mutated oncogenes in human cancers. Despite tremendous efforts over the past several decades, however, RAS-specific inhibitors remain elusive. Thus, targeting RAS remains a highly sought-after goal of cancer research. Previously, we have reported a new approach to inhibit RAS-dependent signaling and transformation in vitro by targeting the alpha 4-alpha 5 dimerization interface with a novel RAS-specific monobody termed NS1. Expression of NS1 inhibits oncogenic K-RAS and H-RAS signaling and transformation in vitro. Here, we evaluated the efficacy of targeting RAS dimerization as an approach to inhibit tumor formation in vivo. Using a doxycycline (DOX)-regulated NS1 expression system, we demonstrate that DOX-induced NS1 inhibited oncogenic K-RAS-driven tumor growth in vivo. Furthermore, we observed context-specific effects of NS1 on RAS-mediated signaling in 2D vs 3D growth conditions. Finally, our results highlight the potential therapeutic efficacy of targeting the alpha 4-alpha 5 dimerization interface as an approach to inhibit RAS-driven tumors in vivo.