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

Autor:	Vidimar V; Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611., Beilhartz GL; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Park M; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Department of Biochemistry, University of Toronto, Toronto, Canada M5S 1A8., Biancucci M; Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611., Kieffer MB; Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611., Gius DR; Department of Radiation Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611.; Robert H. Lurie Comprehensive Cancer Research Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611., Melnyk RA; Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; k-satchell@northwestern.edu roman.melnyk@sickkids.ca.; Department of Biochemistry, University of Toronto, Toronto, Canada M5S 1A8., Satchell KJF; Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611; k-satchell@northwestern.edu roman.melnyk@sickkids.ca.; Robert H. Lurie Comprehensive Cancer Research Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 21; Vol. 117 (29), pp. 16938-16948. Date of Electronic Publication: 2020 Jul 02.
DOI:	10.1073/pnas.2000312117
Abstrakt:	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. Competing Interests: Competing interest statement: M.B. and K.J.F.S. are authors of a pending patent on use of RRSP as a therapeutic for cancer (WO2016019379A1). K.J.F.S. is author of a published patent on use of cysteine protease domain for autoprocessing of proteins (US20100137563A1). R.A.M. and G.L.B. are authors of a published patent on the use of diphtheria toxin for protein delivery and of a pending patent on RRSP-DTB as a RAS-directed therapeutic (US20180080033A1 and WO2019104433A1, respectively). K.J.F.S. has a significant financial interest in Situ Biosciences LLC, which conducts contract research unrelated to this work.
Databáze:	MEDLINE
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