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

被引：36

作者：

Dorard, Coralie ^{[1
,2
,3
,4
,5
]}

Estrada, Charlene ^{[1
,2
,3
,4
,5
]}

Barbotin, Celine ^{[1
,2
,3
,4
,5
]}

Larcher, Magalie ^{[1
,2
,3
,4
,5
]}

Garancher, Alexandra ^{[1
,2
,3
,4
]}

Leloup, Jessy ^{[1
,2
,3
,4
,5
]}

Beermann, Friedrich ^{[6
]}

Baccarini, Manuela ^{[7
]}

Pouponnot, Celio ^{[1
,2
,3
,4
]}

Larue, Lionel ^{[1
,2
,3
,4
,5
]}

Eychene, Alain ^{[1
,2
,3
,4
,5
]}

Druillennec, Sabine ^{[1
,2
,3
,4
,5
]}

机构：

[1] Inst Curie, F-91405 Orsay, France

[2] Ctr Univ, INSERM U1021, F-91405 Orsay, France

[3] Ctr Univ, CNRS UMR 3347, F-91405 Orsay, France

[4] Univ Paris Sud 11, F-91405 Orsay, France

[5] Equipe Labellisee Ligue Natl Canc, F-91405 Orsay, France

[6] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland

[7] Univ Vienna, Ctr Mol Biol, Max F Perutz Labs, A-1030 Vienna, Austria

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

B-RAF; MAPK PATHWAY; C-RAF; CANCER GENOMICS; BRAF MUTATIONS; LUNG-CANCER; ACTIVATION; INHIBITORS; CRAF; RESISTANCE;

D O I：

10.1038/ncomms15262

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13