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Sci Transl Med. 2019 Dec 18;11(523). pii: eaaw1565. doi: 10.1126/scitranslmed.aaw1565.

Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition.

Author information

1
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
3
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. wtao@bwh.harvard.edu tianxie@hznu.edu.cn ofarokhzad@bwh.harvard.edu jshi@bwh.harvard.edu.
4
Department of Cancer Pharmacology, Holistic Integrative Pharmacy Institutes, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
5
Department of Biology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
6
Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
7
Department of Cancer Pharmacology, Holistic Integrative Pharmacy Institutes, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. wtao@bwh.harvard.edu tianxie@hznu.edu.cn ofarokhzad@bwh.harvard.edu jshi@bwh.harvard.edu.
8
King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Abstract

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non-small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

PMID:
31852795
PMCID:
PMC7024563
[Available on 2020-12-18]
DOI:
10.1126/scitranslmed.aaw1565

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