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

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.

authors

Vidimar V,Beilhartz GL,Park M,Biancucci M,Kieffer MB,Gius DR,Melnyk RA,Satchell KJF

doi

10.1073/pnas.2000312117

subject

Has Abstract

pub_date

2020-07-21 00:00:00

pages

16938-16948

issue

29

eissn

0027-8424

issn

1091-6490

pii

2000312117

journal_volume

117

pub_type

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