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Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):E536-45. doi: 10.1073/pnas.1418163112. Epub 2015 Jan 26.

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.

Author information

1
Experimental Cancer Genetics and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
2
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
3
Experimental Cancer Genetics and.
4
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
5
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
6
University of Edinburgh Division of Pathology, Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XR, United Kingdom;
7
Department of Dermatology, Yale University, New Haven, CT 06520;
8
Plexxikon Inc., Berkeley, CA 94710; and.
9
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 dtuveson@cshl.edu da1@sanger.ac.uk.
10
Experimental Cancer Genetics and dtuveson@cshl.edu da1@sanger.ac.uk.

Abstract

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼ 80% of BRAF(V600)-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf(V618E) (analogous to the human BRAF(V600E) mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf(V618E) transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.

KEYWORDS:

BRAF inhibitors; drug resistance; melanoma; mouse models

Comment in

PMID:
25624498
PMCID:
PMC4330752
DOI:
10.1073/pnas.1418163112
[Indexed for MEDLINE]
Free PMC Article
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