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Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants
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 desc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936000/ https://www.ncbi.nlm.nih.gov/pubmed/35139380 http://dx.doi.org/10.1016/j.celrep.2022.110322 |
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author | Khan, Imran Koide, Akiko Zuberi, Mariyam Ketavarapu, Gayatri Denbaum, Eric Teng, Kai Wen Rhett, J. Matthew Spencer-Smith, Russell Hobbs, G. Aaron Camp, Ernest Ramsay Koide, Shohei O’Bryan, John P. |
author_facet | Khan, Imran Koide, Akiko Zuberi, Mariyam Ketavarapu, Gayatri Denbaum, Eric Teng, Kai Wen Rhett, J. Matthew Spencer-Smith, Russell Hobbs, G. Aaron Camp, Ernest Ramsay Koide, Shohei O’Bryan, John P. |
author_sort | Khan, Imran |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8936000 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-89360002022-03-21 Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants Khan, Imran Koide, Akiko Zuberi, Mariyam Ketavarapu, Gayatri Denbaum, Eric Teng, Kai Wen Rhett, J. Matthew Spencer-Smith, Russell Hobbs, G. Aaron Camp, Ernest Ramsay Koide, Shohei O’Bryan, John P. Cell Rep Article 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. 2022-02-08 /pmc/articles/PMC8936000/ /pubmed/35139380 http://dx.doi.org/10.1016/j.celrep.2022.110322 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Khan, Imran Koide, Akiko Zuberi, Mariyam Ketavarapu, Gayatri Denbaum, Eric Teng, Kai Wen Rhett, J. Matthew Spencer-Smith, Russell Hobbs, G. Aaron Camp, Ernest Ramsay Koide, Shohei O’Bryan, John P. Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title | Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title_full | Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title_fullStr | Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title_full_unstemmed | Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title_short | Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants |
title_sort | identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic ras mutants |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936000/ https://www.ncbi.nlm.nih.gov/pubmed/35139380 http://dx.doi.org/10.1016/j.celrep.2022.110322 |
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