An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth

Despite nearly four decades of effort, broad inhibition of onco-genic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endo-peptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concen-trations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mecha-nism represents a promising approach to developing RAS thera-peutics against a broad array of cancers.