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

Abstract

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.

• Authors: Coralie Dorard, Charlène Estrada, Céline Barbotin, Magalie Larcher, Alexandra Garancher, Jessy Leloup, Friedrich Beermann, Manuela Baccarini, Celio Pouponnot, Lionel Larue, Alain Eychène, Sabine Druillennec
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 15262 (05 12 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28497782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Monomeric GTP-Binding Proteins
• Nras protein, mouse
• ras Proteins

Topics

• Animals
• Cell Line, Tumor
• Disease Progression
• Humans
• MAP Kinase Signaling System (genetics)
• Melanoma (genetics, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Monomeric GTP-Binding Proteins (genetics, metabolism)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Proto-Oncogene Proteins c-raf (genetics, metabolism)
• ras Proteins (genetics, metabolism)