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

Jiangsheng Xu; Yunhua Liu; Yujing Li; Hai Wang; Samantha Stewart; Kevin Van der Jeught; Pranay Agarwal; Yuntian Zhang; Sheng Liu; Gang Zhao; Jun Wan; Xiongbin Lu; Xiaoming He

doi:10.1038/s41565-019-0381-6

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

Nat Nanotechnol. 2019 Apr;14(4):388-397. doi: 10.1038/s41565-019-0381-6. Epub 2019 Feb 25.

Authors

Jiangsheng Xu^{1

2

3}, Yunhua Liu^{4

5}, Yujing Li^{4

5}, Hai Wang^{1

2

3}, Samantha Stewart¹, Kevin Van der Jeught^{4

5}, Pranay Agarwal³, Yuntian Zhang^{1

6}, Sheng Liu⁴, Gang Zhao⁶, Jun Wan⁴, Xiongbin Lu^{7

8}, Xiaoming He^{9

10

11

12

13}

Affiliations

¹ Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
² Comprehensive Cancer Centre, The Ohio State University, Columbus, OH, USA.
³ Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
⁴ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Melvin and Bren Simon Cancer Centre, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Electronics Science and Technology, University of Science and Technology of China, Hefei, Anhui, China.
⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. xiolu@iu.edu.
⁸ Melvin and Bren Simon Cancer Centre, Indiana University School of Medicine, Indianapolis, IN, USA. xiolu@iu.edu.
⁹ Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA. shawnhe@umd.edu.
¹⁰ Comprehensive Cancer Centre, The Ohio State University, Columbus, OH, USA. shawnhe@umd.edu.
¹¹ Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA. shawnhe@umd.edu.
¹² Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA. shawnhe@umd.edu.
¹³ Marlene and Stewart Greenebaum Comprehensive Cancer Centre, University of Maryland, Baltimore, MD, USA. shawnhe@umd.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
DNA-Directed RNA Polymerases / metabolism*
Endosomes / metabolism
Female
Gene Deletion
Humans
Hydrogen-Ion Concentration
Lysosomes / metabolism
Mice, Inbred C57BL
Mice, Nude
Nanoparticles / chemistry
Nanoparticles / ultrastructure
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / enzymology*
Triple Negative Breast Neoplasms / pathology
Tumor Suppressor Protein p53 / metabolism

Substances

Tumor Suppressor Protein p53
DNA-Directed RNA Polymerases
POLR2A RNA polymerase, human

Grants and funding

R01 CA206366/CA/NCI NIH HHS/United States