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Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations
BRAF(V600E) melanoma patients, despite initially responding to the clinically prescribed anti-BRAF(V600E) therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAF(V600E) mutation, they often eventually diverge a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192524/ https://www.ncbi.nlm.nih.gov/pubmed/34112933 http://dx.doi.org/10.1038/s41698-021-00190-3 |
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author | Vasudevan, S. Flashner-Abramson, E. Alkhatib, Heba Roy Chowdhury, Sangita Adejumobi, I. A. Vilenski, D. Stefansky, S. Rubinstein, A. M. Kravchenko-Balasha, N. |
author_facet | Vasudevan, S. Flashner-Abramson, E. Alkhatib, Heba Roy Chowdhury, Sangita Adejumobi, I. A. Vilenski, D. Stefansky, S. Rubinstein, A. M. Kravchenko-Balasha, N. |
author_sort | Vasudevan, S. |
collection | PubMed |
description | BRAF(V600E) melanoma patients, despite initially responding to the clinically prescribed anti-BRAF(V600E) therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAF(V600E) mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually. In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAF(V600E) or BRAF(V600E)/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAF(V600E) tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations. |
format | Online Article Text |
id | pubmed-8192524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81925242021-06-28 Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations Vasudevan, S. Flashner-Abramson, E. Alkhatib, Heba Roy Chowdhury, Sangita Adejumobi, I. A. Vilenski, D. Stefansky, S. Rubinstein, A. M. Kravchenko-Balasha, N. NPJ Precis Oncol Article BRAF(V600E) melanoma patients, despite initially responding to the clinically prescribed anti-BRAF(V600E) therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAF(V600E) mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually. In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAF(V600E) or BRAF(V600E)/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAF(V600E) tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations. Nature Publishing Group UK 2021-06-10 /pmc/articles/PMC8192524/ /pubmed/34112933 http://dx.doi.org/10.1038/s41698-021-00190-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Vasudevan, S. Flashner-Abramson, E. Alkhatib, Heba Roy Chowdhury, Sangita Adejumobi, I. A. Vilenski, D. Stefansky, S. Rubinstein, A. M. Kravchenko-Balasha, N. Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title | Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title_full | Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title_fullStr | Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title_full_unstemmed | Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title_short | Overcoming resistance to BRAF(V600E) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
title_sort | overcoming resistance to braf(v600e) inhibition in melanoma by deciphering and targeting personalized protein network alterations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192524/ https://www.ncbi.nlm.nih.gov/pubmed/34112933 http://dx.doi.org/10.1038/s41698-021-00190-3 |
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