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.
Funder
Lynn Sage Cancer Research Foundation
HHS | NIH | National Center for Advancing Translational Sciences
HHS | NIH | National Cancer Institute
NU | Feinberg School of Medicine
NU | Robert H. Lurie Comprehensive Cancer Center
Avon Foundation for Women
Chicago Biomedical Consortium
Chicago Community Trust
Hospital for Sick Children
Gouvernement du Canada | Canadian Institutes of Health Research
Pancreatic Cancer Action Network
Publisher
Proceedings of the National Academy of Sciences
Cited by
27 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献