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

• Published in: Nature nanotechnology Vol. 14; no. 4; pp. 388 - 397
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group
• Subjects: 631/61/350/354; 631/61/54/152; 639/925/352/2733; Animals; Bioavailability; Breast cancer; Cancer; Cell Line, Tumor; Cell Proliferation; Chemistry and Materials Science; DNA-Directed RNA Polymerases - metabolism; Endosomes - metabolism; Female; Gene Deletion; Humans; Hydrogen-Ion Concentration; Inactivation; Lysosomes - metabolism; Materials Science; Mice, Inbred C57BL; Mice, Nude; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Nanotechnology; Nanotechnology and Microengineering; p53 Protein; pH effects; Ribonucleic acid; RNA; siRNA; Therapy; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - enzymology; Triple Negative Breast Neoplasms - pathology; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1748-3387; 1748-3395
• DOI: 10.1038/s41565-019-0381-6

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. Inhibiting POLR2A expression upon siRNA delivery represents a promising therapeutic strategy for triple negative breast cancers characterized by p53 inactivation.