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Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hind...

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Autores principales: Gu, Yihui, Wang, Wei, Li, Yuehua, Li, Haibo, Guo, Zizhen, Wei, Chengjiang, Long, Manmei, Chung, Manhon, Aimaier, Rehanguli, Li, Qingfeng, Wang, Zhichao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303010/
https://www.ncbi.nlm.nih.gov/pubmed/35875109
http://dx.doi.org/10.3389/fonc.2022.903177
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author Gu, Yihui
Wang, Wei
Li, Yuehua
Li, Haibo
Guo, Zizhen
Wei, Chengjiang
Long, Manmei
Chung, Manhon
Aimaier, Rehanguli
Li, Qingfeng
Wang, Zhichao
author_facet Gu, Yihui
Wang, Wei
Li, Yuehua
Li, Haibo
Guo, Zizhen
Wei, Chengjiang
Long, Manmei
Chung, Manhon
Aimaier, Rehanguli
Li, Qingfeng
Wang, Zhichao
author_sort Gu, Yihui
collection PubMed
description Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies.
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spelling pubmed-93030102022-07-22 Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response Gu, Yihui Wang, Wei Li, Yuehua Li, Haibo Guo, Zizhen Wei, Chengjiang Long, Manmei Chung, Manhon Aimaier, Rehanguli Li, Qingfeng Wang, Zhichao Front Oncol Oncology Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies. Frontiers Media S.A. 2022-07-07 /pmc/articles/PMC9303010/ /pubmed/35875109 http://dx.doi.org/10.3389/fonc.2022.903177 Text en Copyright © 2022 Gu, Wang, Li, Li, Guo, Wei, Long, Chung, Aimaier, Li and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Gu, Yihui
Wang, Wei
Li, Yuehua
Li, Haibo
Guo, Zizhen
Wei, Chengjiang
Long, Manmei
Chung, Manhon
Aimaier, Rehanguli
Li, Qingfeng
Wang, Zhichao
Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title_full Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title_fullStr Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title_full_unstemmed Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title_short Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
title_sort preclinical assessment of mek inhibitors for malignant peripheral nerve sheath tumors reveals differences in efficacy and adaptive response
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303010/
https://www.ncbi.nlm.nih.gov/pubmed/35875109
http://dx.doi.org/10.3389/fonc.2022.903177
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