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Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas

Vemurafenib (PLX4032), a selective inhibitor of Braf, has been FDA-approved for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor p...

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Autores principales: Liu, Fang, Cao, Juxiang, Wu, Jinxiang, Sullivan, Kayleigh, Shen, James, Ryu, Byungwoo, Xu, Zhixiang, Wei, Wenyi, Cui, Rutao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9744462/
https://www.ncbi.nlm.nih.gov/pubmed/23344460
http://dx.doi.org/10.1038/jid.2013.32
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author Liu, Fang
Cao, Juxiang
Wu, Jinxiang
Sullivan, Kayleigh
Shen, James
Ryu, Byungwoo
Xu, Zhixiang
Wei, Wenyi
Cui, Rutao
author_facet Liu, Fang
Cao, Juxiang
Wu, Jinxiang
Sullivan, Kayleigh
Shen, James
Ryu, Byungwoo
Xu, Zhixiang
Wei, Wenyi
Cui, Rutao
author_sort Liu, Fang
collection PubMed
description Vemurafenib (PLX4032), a selective inhibitor of Braf, has been FDA-approved for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempt to overcome this resistance by targeting the Stat3-PAX3 signaling pathway, which is upregulated, due to FGF2 secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. Additionally, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.
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spelling pubmed-97444622022-12-12 Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas Liu, Fang Cao, Juxiang Wu, Jinxiang Sullivan, Kayleigh Shen, James Ryu, Byungwoo Xu, Zhixiang Wei, Wenyi Cui, Rutao J Invest Dermatol Article Vemurafenib (PLX4032), a selective inhibitor of Braf, has been FDA-approved for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempt to overcome this resistance by targeting the Stat3-PAX3 signaling pathway, which is upregulated, due to FGF2 secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. Additionally, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma. 2013-08 2013-01-23 /pmc/articles/PMC9744462/ /pubmed/23344460 http://dx.doi.org/10.1038/jid.2013.32 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Liu, Fang
Cao, Juxiang
Wu, Jinxiang
Sullivan, Kayleigh
Shen, James
Ryu, Byungwoo
Xu, Zhixiang
Wei, Wenyi
Cui, Rutao
Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title_full Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title_fullStr Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title_full_unstemmed Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title_short Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
title_sort stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9744462/
https://www.ncbi.nlm.nih.gov/pubmed/23344460
http://dx.doi.org/10.1038/jid.2013.32
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