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Targeted chemotherapy overcomes drug resistance in melanoma

The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We presen...

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Autores principales: Yue, Jingyin, Vendramin, Roberto, Liu, Fan, Lopez, Omar, Valencia, Monica G., Gomes Dos Santos, Helena, Gaidosh, Gabriel, Beckedorff, Felipe, Blumenthal, Ezra, Speroni, Lucia, Nimer, Stephen D., Marine, Jean-Christophe, Shiekhattar, Ramin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197350/
https://www.ncbi.nlm.nih.gov/pubmed/32241802
http://dx.doi.org/10.1101/gad.333864.119
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author Yue, Jingyin
Vendramin, Roberto
Liu, Fan
Lopez, Omar
Valencia, Monica G.
Gomes Dos Santos, Helena
Gaidosh, Gabriel
Beckedorff, Felipe
Blumenthal, Ezra
Speroni, Lucia
Nimer, Stephen D.
Marine, Jean-Christophe
Shiekhattar, Ramin
author_facet Yue, Jingyin
Vendramin, Roberto
Liu, Fan
Lopez, Omar
Valencia, Monica G.
Gomes Dos Santos, Helena
Gaidosh, Gabriel
Beckedorff, Felipe
Blumenthal, Ezra
Speroni, Lucia
Nimer, Stephen D.
Marine, Jean-Christophe
Shiekhattar, Ramin
author_sort Yue, Jingyin
collection PubMed
description The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed “targeted chemotherapy” by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAF(V600E)-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRAS(Q61R)-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAF(V600E) PDX highlighting its effectiveness in combating the advent of drug resistance.
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spelling pubmed-71973502020-05-12 Targeted chemotherapy overcomes drug resistance in melanoma Yue, Jingyin Vendramin, Roberto Liu, Fan Lopez, Omar Valencia, Monica G. Gomes Dos Santos, Helena Gaidosh, Gabriel Beckedorff, Felipe Blumenthal, Ezra Speroni, Lucia Nimer, Stephen D. Marine, Jean-Christophe Shiekhattar, Ramin Genes Dev Research Paper The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed “targeted chemotherapy” by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAF(V600E)-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRAS(Q61R)-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAF(V600E) PDX highlighting its effectiveness in combating the advent of drug resistance. Cold Spring Harbor Laboratory Press 2020-05-01 /pmc/articles/PMC7197350/ /pubmed/32241802 http://dx.doi.org/10.1101/gad.333864.119 Text en © 2020 Yue et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Paper
Yue, Jingyin
Vendramin, Roberto
Liu, Fan
Lopez, Omar
Valencia, Monica G.
Gomes Dos Santos, Helena
Gaidosh, Gabriel
Beckedorff, Felipe
Blumenthal, Ezra
Speroni, Lucia
Nimer, Stephen D.
Marine, Jean-Christophe
Shiekhattar, Ramin
Targeted chemotherapy overcomes drug resistance in melanoma
title Targeted chemotherapy overcomes drug resistance in melanoma
title_full Targeted chemotherapy overcomes drug resistance in melanoma
title_fullStr Targeted chemotherapy overcomes drug resistance in melanoma
title_full_unstemmed Targeted chemotherapy overcomes drug resistance in melanoma
title_short Targeted chemotherapy overcomes drug resistance in melanoma
title_sort targeted chemotherapy overcomes drug resistance in melanoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197350/
https://www.ncbi.nlm.nih.gov/pubmed/32241802
http://dx.doi.org/10.1101/gad.333864.119
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