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Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors
Although BRAF inhibition has demonstrated activity in BRAF(V600)–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary a...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476413/ https://www.ncbi.nlm.nih.gov/pubmed/32843426 http://dx.doi.org/10.1101/mcs.a005041 |
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author | Sen, Shiraj Tanaka, Ryuma Khatua, Soumen Zaky, Wafik Janku, Filip Penas-Prado, Marta Weathers, Shiao-Pei Behrang, Amini Roszik, Jason Subbiah, Vivek |
author_facet | Sen, Shiraj Tanaka, Ryuma Khatua, Soumen Zaky, Wafik Janku, Filip Penas-Prado, Marta Weathers, Shiao-Pei Behrang, Amini Roszik, Jason Subbiah, Vivek |
author_sort | Sen, Shiraj |
collection | PubMed |
description | Although BRAF inhibition has demonstrated activity in BRAF(V600)–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF(V600)-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated. |
format | Online Article Text |
id | pubmed-7476413 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-74764132020-09-18 Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors Sen, Shiraj Tanaka, Ryuma Khatua, Soumen Zaky, Wafik Janku, Filip Penas-Prado, Marta Weathers, Shiao-Pei Behrang, Amini Roszik, Jason Subbiah, Vivek Cold Spring Harb Mol Case Stud Research Report Although BRAF inhibition has demonstrated activity in BRAF(V600)–mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAF(V600)-mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated. Cold Spring Harbor Laboratory Press 2020-08 /pmc/articles/PMC7476413/ /pubmed/32843426 http://dx.doi.org/10.1101/mcs.a005041 Text en © 2020 Sen et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. |
spellingShingle | Research Report Sen, Shiraj Tanaka, Ryuma Khatua, Soumen Zaky, Wafik Janku, Filip Penas-Prado, Marta Weathers, Shiao-Pei Behrang, Amini Roszik, Jason Subbiah, Vivek Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title | Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title_full | Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title_fullStr | Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title_full_unstemmed | Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title_short | Dual inhibition of BRAF and mTOR in BRAF(V600E)-mutant pediatric, adolescent, and young adult brain tumors |
title_sort | dual inhibition of braf and mtor in braf(v600e)-mutant pediatric, adolescent, and young adult brain tumors |
topic | Research Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476413/ https://www.ncbi.nlm.nih.gov/pubmed/32843426 http://dx.doi.org/10.1101/mcs.a005041 |
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