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Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer

TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in...

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Autores principales: Xu, Jiangsheng, Liu, Yunhua, Li, Yujing, Wang, Hai, Stewart, Samantha, Van der Jeught, Kevin, Agarwal, Pranay, Zhang, Yuntian, Liu, Sheng, Zhao, Gang, Wan, Jun, Lu, Xiongbin, He, Xiaoming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449187/
https://www.ncbi.nlm.nih.gov/pubmed/30804480
http://dx.doi.org/10.1038/s41565-019-0381-6
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author Xu, Jiangsheng
Liu, Yunhua
Li, Yujing
Wang, Hai
Stewart, Samantha
Van der Jeught, Kevin
Agarwal, Pranay
Zhang, Yuntian
Liu, Sheng
Zhao, Gang
Wan, Jun
Lu, Xiongbin
He, Xiaoming
author_facet Xu, Jiangsheng
Liu, Yunhua
Li, Yujing
Wang, Hai
Stewart, Samantha
Van der Jeught, Kevin
Agarwal, Pranay
Zhang, Yuntian
Liu, Sheng
Zhao, Gang
Wan, Jun
Lu, Xiongbin
He, Xiaoming
author_sort Xu, Jiangsheng
collection PubMed
description TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53-neighboring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles (siPol2@NPs) leads to enhanced growth reduction of tumours characterised by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.
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spelling pubmed-64491872019-08-25 Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer Xu, Jiangsheng Liu, Yunhua Li, Yujing Wang, Hai Stewart, Samantha Van der Jeught, Kevin Agarwal, Pranay Zhang, Yuntian Liu, Sheng Zhao, Gang Wan, Jun Lu, Xiongbin He, Xiaoming Nat Nanotechnol Article TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53-neighboring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles (siPol2@NPs) leads to enhanced growth reduction of tumours characterised by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration. 2019-02-25 2019-04 /pmc/articles/PMC6449187/ /pubmed/30804480 http://dx.doi.org/10.1038/s41565-019-0381-6 Text en Users 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
Xu, Jiangsheng
Liu, Yunhua
Li, Yujing
Wang, Hai
Stewart, Samantha
Van der Jeught, Kevin
Agarwal, Pranay
Zhang, Yuntian
Liu, Sheng
Zhao, Gang
Wan, Jun
Lu, Xiongbin
He, Xiaoming
Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title_full Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title_fullStr Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title_full_unstemmed Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title_short Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer
title_sort precise targeting of polr2a as a therapeutic strategy for human triple negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449187/
https://www.ncbi.nlm.nih.gov/pubmed/30804480
http://dx.doi.org/10.1038/s41565-019-0381-6
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