Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence.
Level 5 - mechanism / opinion, no new human data
Preclinical cell culture and animal study with no human clinical data.
PubMed 29320480 · doi:10.1038/nature25170
What was done
Investigated the antitumour efficacy of the REV-ERB agonists SR9009 and SR9011 across cultured cancer cell lines with various oncogenic drivers (including HRAS, BRAF, PIK3CA), in p53-deficient and hypoxic environments, and in oncogene-induced senescent cells (melanocytic naevi) versus normal cells. In vivo efficacy, survival effects, and general toxicity were assessed in a mouse glioblastoma model.
What was found
The abstract reports no numerical values, concentrations, or survival statistics. The authors observed that SR9009 and SR9011 selectively killed cancer and senescent cells without affecting normal cell viability, regardless of p53 status or hypoxia. The anticancer mechanism involved apoptotic induction through the inhibition of autophagy and de novo lipogenesis. In vivo, the agonists reduced glioblastoma growth and extended mouse survival without overt toxicity.
Why it matters
This study identifies circadian clock components, specifically REV-ERBα and REV-ERBβ, as actionable drug targets that can exploit metabolic vulnerabilities in cancer cells without harming normal tissues.
Limits
Findings are restricted to cell culture and mouse models, which cannot establish clinical efficacy or safety in humans. The abstract omits sample sizes, quantitative effect sizes, IC50 measurements, and detailed pharmacokinetic parameters.
Cited by
- supports Autophagy flux and autophagy gene expression cycle on a daily basis and are directly regulated by circadian clock components.