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

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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Data availability

All data supporting the findings of this study are available from the corresponding authors upon request.

Additional information

Journal peer review information: Nature Nanotechnology thanks Elsa Flores, Peixuan Guo and other anonymous reviewers for their contribution to the peer review of this work.

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Change history

  • 05 March 2019

    The Supplementary Information originally published with this Article was an older version, in which ‘IFN-γ’ was misspelled ‘INF-γ’ in Supplementary Fig. 9 and the β-Actin blot in Supplementary Fig. 13 was the wrong image. The Supplementary Information has now been replaced.

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Acknowledgements

This work was partially supported by grants from the American Cancer Society (ACS #120936-RSG-11-109-01-CDD) and NIH (R01CA206366) to X.H. and X.L., the Vera Bradley Foundation for Breast Cancer Research to X.L., a Pelotonia post-doctoral fellowship to J.X. and the American Cancer Society Institutional Research Grant to Y. Liu.

Author information

X.H. and X.L. conceived the project and supervised the study. X.H., X.L., J.X. and Y. Liu designed experiments. J.X. and Y. Liu conducted experiments with assistance from Y. Li, H.W., K.V.D.J., P.A., S.L. and J.W. X.H., X.L., J.X., Y. Liu, S.S., Y. Li, K.V.D.J., Y.Z. and G.Z. analysed data. J.X. and Y. Liu wrote the manuscript draft. X.H., X.L. and S.S. edited the manuscript. All authors approved the manuscript.

Competing interests

X.H. and X.L. have applied for patents related to this study.

Correspondence to Xiongbin Lu or Xiaoming He.

Supplementary information

Supplementary Information

Supplementary Figures 1–13, Supplementary notes 1,2, Supplementary references

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Fig. 1: POLR2A is almost always deleted together with TP53 in TNBCs.
Fig. 2: Synthesis and characterization of nanoparticles for stabilizing POLR2A targeting siRNA.
Fig. 3: Low-pH-activated endo/lysosomal escape.
Fig. 4: Nanoparticle-mediated POLR2A inhibition selectively kills POLR2Aloss cells.
Fig. 5: Targeted POLR2A inhibition selectively suppresses the growth of isogenic-cell-derived POLR2Aloss tumours.
Fig. 6: Targeted POLR2A inhibition selectively suppresses the growth of wild-type-cell-derived POLR2Aloss tumours.