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Essential, non-redundant roles of B-Raf and Raf-1 in Ras-driven skin tumorigenesis

Abstract

Ras-driven tumorigenesis is assumed to depend on Raf for ERK activation and proliferation; yet, an in vivo requirement for Raf as MEK/ERK activator in this setting has not been demonstrated to date. Here, we show that epidermis-restricted B-Raf ablation restrains the onset and stops the progression of established Ras-driven tumors by limiting MEK/ERK activation and proliferation. Concomitant elimination of B-Raf and Raf-1 enforces the abrupt regression of established tumors owing to the decrease in ERK activation and proliferation caused by B-Raf ablation combined with the ERK-independent increase in Rho-dependent kinase (Rok) signaling and differentiation triggered by Raf-1 inactivation. Thus, B-Raf and Raf-1 have non-redundant functions in Ras-driven tumorigenesis. Of note, Raf kinase inhibitors achieve impressive results in melanomas harboring oncogenic BRAF, but are ineffective against Ras-driven tumors; moreover, therapy-related skin tumors driven by a paradox ERK activation as well as primary and acquired resistance have been reported. Our results suggest that therapies targeting both Raf kinase-dependent and -independent pathways may be effective against a broader range of malignancies and reduce the risks of adverse effects and/or resistance.

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Acknowledgements

We thank Karin Ehrenreiter and the animal house team for excellent technical help, M Sibilia for the K5-SOS-F mice and P Chambon for the K5-Cre-er(T) animals. This work was supported by European Commission grant LSH-CT-2003–506803 and by Austrian Research Fund grant P19530-B11 (to MB).

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Correspondence to M Baccarini.

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Kern, F., Doma, E., Rupp, C. et al. Essential, non-redundant roles of B-Raf and Raf-1 in Ras-driven skin tumorigenesis. Oncogene 32, 2483–2492 (2013). https://doi.org/10.1038/onc.2012.254

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