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Nature. 2017 Aug 10;548(7666):234-238. doi: 10.1038/nature23291. Epub 2017 Aug 2.

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

Author information

1
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
3
Center for Neural Science, College of Arts and Sciences, New York University, New York, New York 10012, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
5
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
6
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA.
7
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, Madrid 28029, Spain.
8
Molecular Oncology Group, NantOmics, LLC, 9600 Medical Center Drive, Suite 300, Rockville, Maryland 20854, USA.
9
Département de médecine oncologique, Gustave Roussy Cancer Campus, Villejuif, France.
10
Faculté de médecine, Université Paris Sud, Le Kremlin-Bicêtre, France.
11
Urology Department, Saint Joseph Hospital, Paris, France.
12
Anti-Cancer Drug Development Graduate Training Program, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland 21205, USA.
13
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
14
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
15
Center for Mechanism-Based Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Abstract

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

PMID:
28783719
PMCID:
PMC5648058
DOI:
10.1038/nature23291
[Indexed for MEDLINE]
Free PMC Article

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