Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants

Cell Reports

Kai Wen Teng¹  Gayatri Ketavarapu²  Akiko Koide³  Russell Spencer-Smith³  Mariyam Zuberi⁴  J. Matthew Rhett⁵  John P. O'Bryan⁵  Imran Khan⁵  G. Aaron Hobbs⁶  Eric Denbaum⁶  Ernest Ramsay Camp⁶  Shohei Koide⁶ 

[1] Department of Medicine, New York University School of Medicine, New York, NY 10016, USA;Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA;Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA;Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA;Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA;Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA;

关键词: monobody;    anti-RAS biologics;    lung cancer;    pancreatic cancer;    colon cancer;    tumorigenesis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: RAS guanosine triphosphatases (GTPases) are mutated in nearly 20% of human tumors, making them an attractive therapeutic target. Following our discovery that nucleotide-free RAS (apo RAS) regulates cell signaling, we selectively target this state as an approach to inhibit RAS function. Here, we describe the R15 monobody that exclusively binds the apo state of all three RAS isoforms in vitro, regardless of the mutation status, and captures RAS in the apo state in cells. R15 inhibits the signaling and transforming activity of a subset of RAS mutants with elevated intrinsic nucleotide exchange rates (i.e., fast exchange mutants). Intracellular expression of R15 reduces the tumor-forming capacity of cancer cell lines driven by select RAS mutants and KRAS(G12D)-mutant patient-derived xenografts (PDXs). Thus, our approach establishes an opportunity to selectively inhibit a subset of RAS mutants by targeting the apo state with drug-like molecules.

【 授权许可】

Unknown