Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment

Mattia Lauriola, Yehoshua Enuka, Amit Zeisel, Gabriele D’Uva, Lee Roth, Michal Sharon-Sevilla, Moshit Lindzen, Kirti Sharma, Nava Nevo, Morris Feldman, Silvia Carvalho, Hadas Cohen-Dvashi, Merav Kedmi, Nir Ben-Chetrit, Alon Chen, Rossella Solmi, Stefan Wiemann, Fernando Schmitt, Eytan Domany and Yosef Yarden ()
Additional contact information
Mattia Lauriola: Weizmann Institute of Science
Yehoshua Enuka: Weizmann Institute of Science
Amit Zeisel: Weizmann Institute of Science
Gabriele D’Uva: Weizmann Institute of Science
Lee Roth: Weizmann Institute of Science
Michal Sharon-Sevilla: Weizmann Institute of Science
Moshit Lindzen: Weizmann Institute of Science
Kirti Sharma: German Cancer Research Centre (DKFZ)
Nava Nevo: Weizmann Institute of Science
Morris Feldman: Weizmann Institute of Science
Silvia Carvalho: Weizmann Institute of Science
Hadas Cohen-Dvashi: Weizmann Institute of Science
Merav Kedmi: Weizmann Institute of Science
Nir Ben-Chetrit: Weizmann Institute of Science
Alon Chen: Weizmann Institute of Science
Rossella Solmi: Unit of Histology, Embryology and Applied Biology, Diagnostic and Specialty Medicine, Bologna University
Stefan Wiemann: German Cancer Research Centre (DKFZ)
Fernando Schmitt: Faculty of Medicine, University of Toronto
Eytan Domany: Weizmann Institute of Science
Yosef Yarden: Weizmann Institute of Science

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR’s feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.

Date: 2014
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DOI: 10.1038/ncomms6073

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