Time’s up for tumors

Small molecules targeting the circadian clock can wage metabolic war on cancer cells. Circadian rhythms are daily variations in biological function that serve to optimize the metabolic tness of organisms. Longitudinal observations of shift workers indicate that disrupting these rhythms leads to metabolic syndrome and can also predispose individuals to cancer. Moreover, certain “clock genes” that are important for circadian rhythm generation have been identied as tumor suppressors. As such, it has long been hoped that the connection between circadian rhythms and cancer could be harnessed to treat patients. In a recent study, Sulli et al. provide evidence that pharmacological targeting of circadian clock genes could be effective as a cancer chemotherapy. Treatment of a variety of cancer cell types with SR9009 and SR9011, two small molecule agonists of REV-ERBa and REV-ERBß, led to cancer cell death but did not affect the viability of nontransformed cells. REV-ERBa/ß are molecular components of circadian clock that serve primarily as transcriptional repressors. The authors determined that SR9009 and SR9011 kill tumor cells by disrupting their metabolism via two mechanisms. The rst is by inhibiting de novo lipid biosynthesis through repression of steroyl-CoA desaturase expression, leading to a deciency of oleic acid. The second is by inhibiting autophagy, a catabolic pathway necessary for cells to survive nutrient-limited conditions. The authors demonstrated the in vivo ecacy of REV-ERBa/ß agonists, showing that SR9009 can slow tumor growth and promote survival in a mouse model of glioblastoma. The authors suggest that the low toxicity of SR9009 and SR9011 is due to the heightened tumor cells dependence on autophagy and local lipid biosynthesis. However, the high doses of SR9009 needed to yield results in vivo (200 mg/kg) suggest that more potent REV-ERB agonists might be needed to enable human trials. Regardless, the results of Sulli et al. may represent a major advance in translating a long-observed connection between circadian rhythms and cancer into a novel therapy.