Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations

Abstract BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E mutation, they often eventually diverg...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	S. Vasudevan, E. Flashner-Abramson, Heba Alkhatib, Sangita Roy Chowdhury, I. A. Adejumobi, D. Vilenski, S. Stefansky, A. M. Rubinstein, N. Kravchenko-Balasha
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3fa3ce4bd8c843c780d29b16c0e89e36
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3fa3ce4bd8c843c780d29b16c0e89e36
record_format	dspace
spelling	oai:doaj.org-article:3fa3ce4bd8c843c780d29b16c0e89e362021-12-02T17:34:47ZOvercoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations10.1038/s41698-021-00190-32397-768Xhttps://doaj.org/article/3fa3ce4bd8c843c780d29b16c0e89e362021-06-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00190-3https://doaj.org/toc/2397-768XAbstract BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E 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-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E 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.S. VasudevanE. Flashner-AbramsonHeba AlkhatibSangita Roy ChowdhuryI. A. AdejumobiD. VilenskiS. StefanskyA. M. RubinsteinN. Kravchenko-BalashaNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 S. Vasudevan E. Flashner-Abramson Heba Alkhatib Sangita Roy Chowdhury I. A. Adejumobi D. Vilenski S. Stefansky A. M. Rubinstein N. Kravchenko-Balasha Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
description	Abstract BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E 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-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E 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	article
author	S. Vasudevan E. Flashner-Abramson Heba Alkhatib Sangita Roy Chowdhury I. A. Adejumobi D. Vilenski S. Stefansky A. M. Rubinstein N. Kravchenko-Balasha
author_facet	S. Vasudevan E. Flashner-Abramson Heba Alkhatib Sangita Roy Chowdhury I. A. Adejumobi D. Vilenski S. Stefansky A. M. Rubinstein N. Kravchenko-Balasha
author_sort	S. Vasudevan
title	Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
title_short	Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
title_full	Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
title_fullStr	Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
title_full_unstemmed	Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations
title_sort	overcoming resistance to brafv600e inhibition in melanoma by deciphering and targeting personalized protein network alterations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3fa3ce4bd8c843c780d29b16c0e89e36
work_keys_str_mv	AT svasudevan overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT eflashnerabramson overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT hebaalkhatib overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT sangitaroychowdhury overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT iaadejumobi overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT dvilenski overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT sstefansky overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT amrubinstein overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations AT nkravchenkobalasha overcomingresistancetobrafv600einhibitioninmelanomabydecipheringandtargetingpersonalizedproteinnetworkalterations
_version_	1718379935567970304

Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations

Ejemplares similares