Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence
Gabriele Sulli1, Amy Rommel2, Xiaojie Wang3
1Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Abstract:
The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. 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 clock. 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.
Insights
REV-ERB agonists SR9009 and SR9011 selectively kill cancer cells by disrupting circadian rhythms, offering a new therapeutic strategy. These compounds show potent anticancer effects without harming normal cells.
Area of Science:
- Chronobiology
- Molecular Oncology
- Pharmacology
Background:
- Circadian clock disruption is linked to cancer development.
- Pharmacological targeting of the circadian machinery is a potential cancer therapy.
- REV-ERB nuclear receptors are key circadian clock components.
Purpose of the Study:
- To investigate the anticancer potential of REV-ERB agonists.
- To determine the mechanism of action and selectivity of REV-ERB agonists.
- To evaluate the efficacy and toxicity of REV-ERB agonists in preclinical models.
Main Methods:
- Treatment of cancer cells and normal cells with REV-ERB agonists SR9009 and SR9011.
- Assessment of cell viability, apoptosis, autophagy, and de novo lipogenesis.
- In vivo studies using mouse models of glioblastoma.
Main Results:
- SR9009 and SR9011 selectively induce apoptosis in cancer cells and senescent cells, sparing normal cells.
- Anticancer activity is observed across various oncogenic drivers, p53-deficient, and hypoxic conditions.
- REV-ERB agonists inhibit autophagy and de novo lipogenesis, leading to cancer cell death.
- In vivo, these agonists reduced glioblastoma growth and improved survival with no overt toxicity.
Conclusions:
- REV-ERB agonists represent a promising class of anticancer agents with selective toxicity towards neoplasms.
- Pharmacological modulation of circadian regulators offers an effective antitumour strategy.
- REV-ERB agonists have a broad therapeutic window and potential for treating various cancers.
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