| First Author | Kern F | Year | 2013 |
| Journal | Oncogene | Volume | 32 |
| Issue | 19 | Pages | 2483-92 |
| PubMed ID | 22733131 | Mgi Jnum | J:198025 |
| Mgi Id | MGI:5495101 | Doi | 10.1038/onc.2012.254 |
| Citation | Kern F, et al. (2013) Essential, non-redundant roles of B-Raf and Raf-1 in Ras-driven skin tumorigenesis. Oncogene 32(19):2483-92 |
| abstractText | 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. |
