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|Ref Type||Journal Article|
|Authors||Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, Plikus MV, Verma IM, Panda S|
|Title||Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence.|
|Date||2018 Jan 18|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|SR9009||SR9009 is a synthetic agonist of REV-ERB nuclear receptors that may lead to suppression of tumorigenesis processes (PMID: 29320480).|
|SR9011||SR9011 is a synthetic agonist of REV-ERB nuclear receptors that may lead to suppression of tumorigenesis processes (PMID: 29320480).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||SR9011||Preclinical - Cell culture||Actionable||In a preclinicl study SR9011 demonstrated toxicity in a wide range of tumor cell lines harboring different driver mutations, but not in normal cell lines in culture (PMID: 29320480).||29320480|
|Unknown unknown||glioblastoma multiforme||not applicable||SR9009||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, SR9009 inhibited growth of glioblastoma cell lines in culture, resulted in apoptosis in tumors and prolonged survival in both cell line and patient-derived xenograft models (PMID: 29320480).||29320480|
|Unknown unknown||Advanced Solid Tumor||not applicable||SR9009||Preclinical - Cell culture||Actionable||In a preclinicl study SR9009 demonstrated toxicity in a wide range of tumor cell lines harboring different driver mutations, but not in normal cell lines in culture (PMID: 29320480).||29320480|
|HRAS G12V||Advanced Solid Tumor||predicted - sensitive||SR9011||Preclinical - Cell culture||Actionable||In a preclinical study, SR9011 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480).||29320480|
|HRAS G12V||Advanced Solid Tumor||predicted - sensitive||SR9009||Preclinical - Cell culture||Actionable||In a preclinical study, SR9009 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480).||29320480|