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

Abstract

The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response ^{1, 2} . Perturbations of these processes are hallmarks of cancer ³ and chronic circadian rhythm disruption predisposes to tumor development ^{1, 4} . This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combatting cancer. The nuclear hormone receptors REV-ERBα and REV-ERBβ (REV-ERBs) are essential components of the circadian clock ^{5, 6} . Here we show that SR9009 and SR9011, two different agonists of REV-ERBs are specifically lethal to cancer cells and oncogene-induced senescent (OIS) cells, including melanocytic naevi, while having no effect on viability of normal cells or tissues. Anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as H-RAS, 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 plays a critical role in evoking an apoptotic response in malignant cells. Importantly, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing any overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective novel antitumor strategy, identifying the existence of a previously unknown class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are novel autophagy and de novo lipogenesis inhibitors with selective activity towards malignant and benign neoplasms.