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

Nature Nanotechnology
Jiangsheng XuXiaoming He

Abstract

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-neighbouring 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 leads to enhanced growth reduction of tumours characterized 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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Citations

Jan 7, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Zhanxia ZhangLijun Jia
Jun 18, 2020·Advanced Healthcare Materials·Jiangsheng XuXiaoming He
Oct 4, 2020·IET Nanobiotechnology·Hasnat Tariq, Syed Ali Imran Bokhari
May 26, 2020·Advanced Drug Delivery Reviews·Jianfeng Guo, Leaf Huang
Sep 1, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jinjin WangXing-Jie Liang
Feb 10, 2021·ACS Biomaterials Science & Engineering·Mingchao LiYan-Qing Guan
Feb 12, 2021·Science Translational Medicine·Yujing LiXiongbin Lu
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Dec 29, 2020·International Journal of Nanomedicine·Wenjing PeiChengcheng Niu
Feb 23, 2021·Asian Journal of Pharmaceutical Sciences·Huan WangChangyou Zhan
Mar 23, 2021·Advanced Science·Tie Chang, Gang Zhao
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May 22, 2021·Advanced Drug Delivery Reviews·Zehua LiuHélder A Santos
Jun 23, 2020·Biomacromolecules·Raut BholakantWei Chen
Sep 23, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Kailong ZhangLongxin Qiu
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Methods Mentioned

BETA
PCR
transmission electron microscopy
dynamic light scattering
X-ray
xenograft
fluorescence imaging

Software Mentioned

ImageJ
cBioportal
GraphPad
POLR2A
JACoP
Prism

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