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Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment

A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a...

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Autores principales: Friedman, Adam A., Amzallag, Arnaud, Pruteanu-Malinici, Iulian, Baniya, Subash, Cooper, Zachary A., Piris, Adriano, Hargreaves, Leeza, Igras, Vivien, Frederick, Dennie T., Lawrence, Donald P., Haber, Daniel A., Flaherty, Keith T., Wargo, Jennifer A., Ramaswamy, Sridhar, Benes, Cyril H., Fisher, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604168/
https://www.ncbi.nlm.nih.gov/pubmed/26461489
http://dx.doi.org/10.1371/journal.pone.0140310
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author Friedman, Adam A.
Amzallag, Arnaud
Pruteanu-Malinici, Iulian
Baniya, Subash
Cooper, Zachary A.
Piris, Adriano
Hargreaves, Leeza
Igras, Vivien
Frederick, Dennie T.
Lawrence, Donald P.
Haber, Daniel A.
Flaherty, Keith T.
Wargo, Jennifer A.
Ramaswamy, Sridhar
Benes, Cyril H.
Fisher, David E.
author_facet Friedman, Adam A.
Amzallag, Arnaud
Pruteanu-Malinici, Iulian
Baniya, Subash
Cooper, Zachary A.
Piris, Adriano
Hargreaves, Leeza
Igras, Vivien
Frederick, Dennie T.
Lawrence, Donald P.
Haber, Daniel A.
Flaherty, Keith T.
Wargo, Jennifer A.
Ramaswamy, Sridhar
Benes, Cyril H.
Fisher, David E.
author_sort Friedman, Adam A.
collection PubMed
description A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAF(V600E) mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.
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spelling pubmed-46041682015-10-20 Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment Friedman, Adam A. Amzallag, Arnaud Pruteanu-Malinici, Iulian Baniya, Subash Cooper, Zachary A. Piris, Adriano Hargreaves, Leeza Igras, Vivien Frederick, Dennie T. Lawrence, Donald P. Haber, Daniel A. Flaherty, Keith T. Wargo, Jennifer A. Ramaswamy, Sridhar Benes, Cyril H. Fisher, David E. PLoS One Research Article A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAF(V600E) mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations. Public Library of Science 2015-10-13 /pmc/articles/PMC4604168/ /pubmed/26461489 http://dx.doi.org/10.1371/journal.pone.0140310 Text en © 2015 Friedman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Friedman, Adam A.
Amzallag, Arnaud
Pruteanu-Malinici, Iulian
Baniya, Subash
Cooper, Zachary A.
Piris, Adriano
Hargreaves, Leeza
Igras, Vivien
Frederick, Dennie T.
Lawrence, Donald P.
Haber, Daniel A.
Flaherty, Keith T.
Wargo, Jennifer A.
Ramaswamy, Sridhar
Benes, Cyril H.
Fisher, David E.
Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title_full Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title_fullStr Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title_full_unstemmed Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title_short Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment
title_sort landscape of targeted anti-cancer drug synergies in melanoma identifies a novel braf-vegfr/pdgfr combination treatment
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604168/
https://www.ncbi.nlm.nih.gov/pubmed/26461489
http://dx.doi.org/10.1371/journal.pone.0140310
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