PMID- 31852795 OWN - NLM STAT- MEDLINE DCOM- 20200914 LR - 20211204 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 11 IP - 523 DP - 2019 Dec 18 TI - Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. LID - 10.1126/scitranslmed.aaw1565 [doi] LID - eaaw1565 AB - 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. CI - Copyright (c) 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Kong, Na AU - Kong N AUID- ORCID: 0000-0002-3823-8335 AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. AD - School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China. FAU - Tao, Wei AU - Tao W AUID- ORCID: 0000-0002-4277-3728 AD - 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. FAU - Ling, Xiang AU - Ling X AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Wang, Junqing AU - Wang J AUID- ORCID: 0000-0002-9091-9891 AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Xiao, Yuling AU - Xiao Y AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Shi, Sanjun AU - Shi S AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Ji, Xiaoyuan AU - Ji X AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. AD - Department of Cancer Pharmacology, Holistic Integrative Pharmacy Institutes, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. FAU - Shajii, Aram AU - Shajii A AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Gan, Silvia Tian AU - Gan ST AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. AD - Department of Biology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada. FAU - Kim, Na Yoon AU - Kim NY AUID- ORCID: 0000-0001-6169-7452 AD - Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Duda, Dan G AU - Duda DG AUID- ORCID: 0000-0001-7065-8797 AD - Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. FAU - Xie, Tian AU - Xie T AUID- ORCID: 0000-0003-4368-760X AD - 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. FAU - Farokhzad, Omid C AU - Farokhzad OC AUID- ORCID: 0000-0003-2009-270X AD - 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. AD - King Abdulaziz University, Jeddah 21589, Saudi Arabia. FAU - Shi, Jinjun AU - Shi J AUID- ORCID: 0000-0001-9200-5068 AD - 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. LA - eng GR - P30 CA006516/CA/NCI NIH HHS/United States GR - P30 NS072030/NS/NINDS NIH HHS/United States GR - R01 CA200900/CA/NCI NIH HHS/United States GR - R25 CA174650/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (RNA, Messenger) RN - 0 (Tumor Suppressor Protein p53) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Cell Line, Tumor MH - Enzyme-Linked Immunosorbent Assay MH - Everolimus/therapeutic use MH - Female MH - Fluorescent Antibody Technique MH - Humans MH - Mice, Inbred C57BL MH - Mice, Nude MH - Microscopy, Electron, Transmission MH - Nanoparticles/chemistry/metabolism MH - Neoplasms/drug therapy/genetics/*metabolism MH - RNA, Messenger/genetics/*metabolism MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Tumor Suppressor Protein p53/genetics/*metabolism PMC - PMC7024563 MID - NIHMS1555938 EDAT- 2019/12/20 06:00 MHDA- 2020/09/15 06:00 PMCR- 2020/12/18 CRDT- 2019/12/20 06:00 PHST- 2018/12/02 00:00 [received] PHST- 2019/08/23 00:00 [revised] PHST- 2019/11/20 00:00 [accepted] PHST- 2019/12/20 06:00 [entrez] PHST- 2019/12/20 06:00 [pubmed] PHST- 2020/09/15 06:00 [medline] PHST- 2020/12/18 00:00 [pmc-release] AID - 11/523/eaaw1565 [pii] AID - 10.1126/scitranslmed.aaw1565 [doi] PST - ppublish SO - Sci Transl Med. 2019 Dec 18;11(523):eaaw1565. doi: 10.1126/scitranslmed.aaw1565.