@article{7ba5ae19301d4a608755db26aa6f1b52,
title = "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.",
keywords = "Cancer, RAS, RRSP, Recombinant toxins, Xenograft",
author = "Vania Vidimar and Beilhartz, {Greg L.} and Minyoung Park and Marco Biancucci and Kieffer, {Matthew B.} and Gius, {David R.} and Melnyk, {Roman A.} and Satchell, {Karla J.F.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank the Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility and B. Shmaltuyeva, B. Frederick, and Dr. D. Gursel for assistance with immunohistochemical staining; A. Dean and C. Nordloh for assistance with xenografts; S. Son for performing validation of the pan-RAS antibody; Dr. Damiano Fantini for bioinformatics assistance; and the Frederick National Laboratory for Cancer Research (FNLCR) for providing the RAS-less KRASWT MEF cells and the anti-RAS 4E8 hybridoma cells. This work was funded by the Lynn Sage Cancer Research Foundation; Northwestern University Clinical and Translational Sciences Institute (which is supported by NIH/National Center for Advancing Translational Sciences Award UL1TR001422); the Northwestern Medicine Catalyst Fund; and the Robert H. Lurie Comprehensive Cancer Research Center (to K.J.F.S.). D.R.G. is supported by NIH/NCI Grants R01CA152601, R01CA152799, R01CA168292, and R01CA214025, the Avon Breast Cancer Foundation, the Zell Family Foundation, the Chicago Biomedical Consortium, and the Searle Funds at The Chicago Community Trust. Additional support from the SickKids Proof-of-Principal Funding and the Canadian Institutes of Health Research Grant 366017 (to R.A.M.). M.B. was supported by a PanCan/FNLCR Fellowship. G.L.B. was supported by a SickKids Restracomp Fellowship. Funding Information: We thank the Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility and B. Shmaltuyeva, B. Frederick, and Dr. D. Gursel for assistance with immunohistochemical staining; A. Dean and C. Nordloh for assistance with xenografts; S. Son for performing validation of the pan-RAS antibody; Dr. Damiano Fantini for bioinformatics assistance; and the Frederick National Laboratory for Cancer Research (FNLCR) for providing the RAS-less KRASWT MEF cells and the anti-RAS 4E8 hybridoma cells. This work was funded by the Lynn Sage Cancer Research Foundation; Northwestern University Clinical and Translational Sciences Institute (which is supported by NIH/National Center for Advancing Translational Sciences Award UL1TR001422); the Northwestern Medicine Catalyst Fund; and the Robert H. Lurie Comprehensive Cancer Research Center (to K.J.F.S.). D.R.G. is supported by NIH/NCI Grants R01CA152601, R01CA152799, R01CA168292, and R01CA214025, the Avon Breast Cancer Foundation, the Zell Family Foundation, the Chicago Biomedical Consortium, and the Searle Funds at The Chicago Community Trust. Additional support from the SickKids Proof-of-Principal Funding and the Canadian Institutes of Health Research Grant 366017 (to R.A.M.). M.B. was supported by a PanCan/FNLCR Fellowship. G.L.B. was supported by a SickKids Restracomp Fellowship. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jul,
day = "21",
doi = "10.1073/pnas.2000312117",
language = "English (US)",
volume = "117",
pages = "16938--16948",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "29",
}
