National Academy of Sciences, Proceedings of the National Academy of Sciences, 29(117), p. 16938-16948, 2020
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Significance RAS oncoproteins have long been considered among the most elusive drug targets in cancer research. At issue is the lack of accessible drug-binding sites and the extreme affinity for GTP. Covalent inhibitors against the KRAS G12C mutant have shown early clinical promise; however, targeting the other oncogenic RAS mutants across three RAS isoforms has proven challenging. Inhibition of activated wild-type RAS in the absence of canonical RAS mutations is also highly desirable in certain tumors. Here, we demonstrate delivery of an extremely potent pan-RAS and RAP1-cleaving enzyme in therapeutic quantities to specific receptor-bearing cells in vitro and in vivo. We aim to advance this approach to engineer the first targeted pan-RAS inhibitor for cancer therapy.