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Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma

BRAF and MEK inhibitors significantly prolong progression-free survival in patients with BRAF mutant melanoma. However, most patients quickly develop drug resistance. The mechanism of drug resistance is complicated and remains to be further explored. Here, we found that inhibition of the MAPK pathwa...

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Autores principales: Zhao, Kun, Lu, Yanrong, Chen, Younan, Cheng, Jingqiu, Zhang, Wengeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330142/
https://www.ncbi.nlm.nih.gov/pubmed/32637584
http://dx.doi.org/10.1016/j.omto.2020.06.004
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author Zhao, Kun
Lu, Yanrong
Chen, Younan
Cheng, Jingqiu
Zhang, Wengeng
author_facet Zhao, Kun
Lu, Yanrong
Chen, Younan
Cheng, Jingqiu
Zhang, Wengeng
author_sort Zhao, Kun
collection PubMed
description BRAF and MEK inhibitors significantly prolong progression-free survival in patients with BRAF mutant melanoma. However, most patients quickly develop drug resistance. The mechanism of drug resistance is complicated and remains to be further explored. Here, we found that inhibition of the MAPK pathway activates the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, whereas JAK2 inhibitors that inhibit the JAK2/STAT3 pathway activate the MAPK pathway, suggesting a crosstalk between these two pathways in BRAF mutant melanoma cells. Reactivation of the MAPK pathway occurs in most drug-resistant patients with BRAF mutations. Therefore, dual inhibition of the MAPK and JAK2/STAT3 pathways is critical for the treatment of BRAF mutant melanoma. However, we found that the combination of BRAF, MEK inhibitors, and JAK2 or STAT3 inhibitors could not simultaneously inhibit the MAPK and JAK2/STAT3 pathways in BRAF mutant melanoma cells. Subsequently, we found that a combination of all three MAPK pathway inhibitors—BRAF, MEK, and ERK inhibitors—with JAK2 or STAT3 inhibitors can dually inhibit the MAPK and JAK2/STAT3 pathways, showing a significant inhibition of the growth of BRAF mutant melanoma cells compared with either treatment alone. Therefore, dual inhibition of MAPK and JAK2/STAT3 pathways may be a novel strategy for the treatment of BRAF mutant tumors.
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spelling pubmed-73301422020-07-06 Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma Zhao, Kun Lu, Yanrong Chen, Younan Cheng, Jingqiu Zhang, Wengeng Mol Ther Oncolytics Article BRAF and MEK inhibitors significantly prolong progression-free survival in patients with BRAF mutant melanoma. However, most patients quickly develop drug resistance. The mechanism of drug resistance is complicated and remains to be further explored. Here, we found that inhibition of the MAPK pathway activates the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, whereas JAK2 inhibitors that inhibit the JAK2/STAT3 pathway activate the MAPK pathway, suggesting a crosstalk between these two pathways in BRAF mutant melanoma cells. Reactivation of the MAPK pathway occurs in most drug-resistant patients with BRAF mutations. Therefore, dual inhibition of the MAPK and JAK2/STAT3 pathways is critical for the treatment of BRAF mutant melanoma. However, we found that the combination of BRAF, MEK inhibitors, and JAK2 or STAT3 inhibitors could not simultaneously inhibit the MAPK and JAK2/STAT3 pathways in BRAF mutant melanoma cells. Subsequently, we found that a combination of all three MAPK pathway inhibitors—BRAF, MEK, and ERK inhibitors—with JAK2 or STAT3 inhibitors can dually inhibit the MAPK and JAK2/STAT3 pathways, showing a significant inhibition of the growth of BRAF mutant melanoma cells compared with either treatment alone. Therefore, dual inhibition of MAPK and JAK2/STAT3 pathways may be a novel strategy for the treatment of BRAF mutant tumors. American Society of Gene & Cell Therapy 2020-06-05 /pmc/articles/PMC7330142/ /pubmed/32637584 http://dx.doi.org/10.1016/j.omto.2020.06.004 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Zhao, Kun
Lu, Yanrong
Chen, Younan
Cheng, Jingqiu
Zhang, Wengeng
Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title_full Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title_fullStr Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title_full_unstemmed Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title_short Dual Inhibition of MAPK and JAK2/STAT3 Pathways Is Critical for the Treatment of BRAF Mutant Melanoma
title_sort dual inhibition of mapk and jak2/stat3 pathways is critical for the treatment of braf mutant melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330142/
https://www.ncbi.nlm.nih.gov/pubmed/32637584
http://dx.doi.org/10.1016/j.omto.2020.06.004
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