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PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN

Targeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatmen...

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Autores principales: Qin, Yifei, Zuo, Qiang, Huang, Lei, Huang, Liping, Merlino, Glenn, Yu, Yanlin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289936/
https://www.ncbi.nlm.nih.gov/pubmed/34282258
http://dx.doi.org/10.1038/s41698-021-00207-x
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author Qin, Yifei
Zuo, Qiang
Huang, Lei
Huang, Liping
Merlino, Glenn
Yu, Yanlin
author_facet Qin, Yifei
Zuo, Qiang
Huang, Lei
Huang, Liping
Merlino, Glenn
Yu, Yanlin
author_sort Qin, Yifei
collection PubMed
description Targeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses.
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spelling pubmed-82899362021-07-23 PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN Qin, Yifei Zuo, Qiang Huang, Lei Huang, Liping Merlino, Glenn Yu, Yanlin NPJ Precis Oncol Article Targeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses. Nature Publishing Group UK 2021-07-19 /pmc/articles/PMC8289936/ /pubmed/34282258 http://dx.doi.org/10.1038/s41698-021-00207-x Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Qin, Yifei
Zuo, Qiang
Huang, Lei
Huang, Liping
Merlino, Glenn
Yu, Yanlin
PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title_full PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title_fullStr PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title_full_unstemmed PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title_short PERK mediates resistance to BRAF inhibition in melanoma with impaired PTEN
title_sort perk mediates resistance to braf inhibition in melanoma with impaired pten
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289936/
https://www.ncbi.nlm.nih.gov/pubmed/34282258
http://dx.doi.org/10.1038/s41698-021-00207-x
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