4 years ago

RAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma

RAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma
Charlène Estrada, Magalie Larcher, Alexandra Garancher, Friedrich Beermann, Manuela Baccarini, Alain Eychène, Céline Barbotin, Lionel Larue, Sabine Druillennec, Jessy Leloup, Coralie Dorard, Celio Pouponnot
NRAS and its effector BRAF are frequently mutated in melanoma. Paradoxically, CRAF but not BRAF was shown to be critical for various RAS-driven cancers, raising the question of the role of RAF proteins in NRAS-induced melanoma. Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance. We show that BRAF expression is required for ERK activation and nevi development, demonstrating a critical role in the early stages of NRAS-driven melanoma. After melanoma formation, single Braf or Craf ablation is not sufficient to block tumour growth, showing redundant functions for RAF kinases. Finally, proliferation of resistant cells emerging in the absence of BRAF and CRAF remains dependent on ARAF-mediated ERK activation. These results reveal specific and compensatory functions for BRAF and CRAF and highlight an addiction to RAF signalling in NRAS-driven melanoma.

Publisher URL: http://www.nature.com/articles/ncomms15262

DOI: 10.1038/ncomms15262

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