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

Vania Vidimar, Greg L. Beilhartz, Minyoung Park, Marco Biancucci, Matthew B. Kieffer, David R. Gius, Roman A. Melnyk*, Karla J.F. Satchell

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Despite nearly four decades of effort, broad inhibition of oncogenic 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 endopeptidase 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 concentrations 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 mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.

Original languageEnglish (US)
Pages (from-to)16938-16948
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number29
DOIs
StatePublished - Jul 21 2020

Keywords

  • Cancer
  • RAS
  • RRSP
  • Recombinant toxins
  • Xenograft

ASJC Scopus subject areas

  • General

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