REV-ERB Agonists Block Autophagy in Cancer Cells

The circadian clock coordinates diverse cellular processes including cell proliferation, metabolism, inflammation, and the DNA damage response. Consequently, circadian rhythm disruption elevates the risk of cancer, suggesting the possibility for pharmacologic modulation of circadian clock components in cancer therapy. The nuclear hormone receptors REV-ERBα and REV-ERBβ are essential circadian clock repressors, and recently two REV-ERB agonists, SR9009 and SR9011, with in vivo activity have been developed. These compounds allowed Sulli and colleagues to investigate the effects of circadian clock pharmacologic modulation on cancer cell viability. Both SR9009 and SR9011 induced apoptosis in a variety of cancer cell lines including brain, breast, and colon cancers, melanoma, and leukemia, and including cells driven by HRAS, KRAS, BRAF, or β-catenin, or by PTEN deficiency, with little toxicity to normal cells. Cancer cells depend on autophagy, which exhibits a circadian regulation controlled by REV-ERBα, prompting investigation of the effects of REV-ERB agonism on autophagy. Treatment with SR9009 or SR9011 reduced the number of autophagosomes and increased accumulation of lysosomes and p62 (a protein degraded by autophagy), suggesting that REV-ERB agonism inhibits autophagy. REV-ERB agonism also blocked autophagy and induced apoptosis in cells that had undergone oncogene-induced senescence. In vivo, SR9009 triggered apoptosis in NRAS-driven nevi, benign lesions comprised of cutaneous melanocytes that have undergone oncogene-induced senescence. Further, SR9009, which can cross the blood–brain barrier, suppressed glioblastoma growth in vivo. In addition to suggesting that pharmacologic modulation of circadian clock components may be a potential strategy for the treatment of patients with cancer, these findings support further investigation of REV-ERB agonists as anticancer therapeutics.

Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 2018;553:351–5.

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