Letter | Published:

Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence

Nature volume 553, pages 351355 (18 January 2018) | Download Citation

Abstract

The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response1,2. Perturbations of these processes are hallmarks of cancer3 and chronic circadian rhythm disruption predisposes individuals to tumour development1,4. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock5,6. Here we show that two agonists of REV-ERBs—SR9009 and SR9011—are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms.

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Acknowledgements

We thank K. V. Ly, L. Fijany, Y. Soda, M. Soda and M. Schmitt for technical assistance; F. d’Adda di Fagagna, S. Minucci, A. Viale, G. Gargiulo and J. Karlseder for discussion and feedback; the Narita, Gage, Burris, Amati and Shaw laboratories, and F. F. Lang for reagents; and the Salk Institute’s Waitt Advanced Biophotonics Center and Gene Targeting and Transfer, and M. Shokhirev and the Razavi Newman Integrative Genomics and Bioinformatics Core. G.S. is supported by the AIRC/Marie Curie International Fellowships in Cancer Research (12298), Istituto Superiore di Sanità, TRAIN ‘Training through Research Application Italian iNitiative’. M.V.P. is supported by the NIH (NIAMS grants R01-AR067273 and R01-AR069653) and a Pew Charitable Trust grant. X.W. is supported by a CIHR postdoctoral fellowship (MFE-123724). I.M.V is an American Cancer Society Professor of Molecular Biology. A.R. is supported by the NCI T32 grant, Salk Women in Science, Salk Excellerators Award and the Stavros Niarchos Foundation New Frontiers Salk Research Specialist Award. M.J.K. is supported by F30 DK112604. A.S. is supported by the NCI Cancer Center Support Grant P30 (CA014195 MASS core) and Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals. This work was supported in part by a Worldwide Cancer Research grant and an American Federation of Aging Research mid-career grant M14322 to S.P. Additional support came from a Cancer Center Core Grant (P30 CA014195-38), the H. N. and Frances C. Berger Foundation, the Glenn Center for Aging Research and the Leona M. and Harry B. Helmsley Charitable Trust (grant #2012-PG-MED002).

Author information

Affiliations

  1. Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Gabriele Sulli
    •  & Satchidananda Panda
  2. Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Amy Rommel
    •  & Inder M. Verma
  3. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697, USA

    • Xiaojie Wang
    •  & Maksim V. Plikus
  4. Clayton Foundation Laboratories of Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Matthew J. Kolar
    •  & Alan Saghatelian
  5. Department of Genomic Medicine, The University of Texas MD, Anderson Cancer Center, Houston, Texas 77030, USA

    • Francesca Puca

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Contributions

X.W. and M.V.P. performed experiments related to naevi. A.R. participated in xenograft experiments. F.P. performed experiments in Extended Data Figs 8g–l, 10h–j. M.J.K. performed lipidomic assays. G.S. designed the study, performed experiments, analysed data and wrote the manuscript. A.S, I.M.V. and M.V.P. supervised experiments and edited the manuscript. S.P. supervised, designed the study and reviewed the data and manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gabriele Sulli or Satchidananda Panda.

Reviewer Information Nature thanks S. Kay, L. Zender and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    Supplementary Information

    This file contains the full scans of the immunoblots used in the figures.

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DOI

https://doi.org/10.1038/nature25170

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