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

Perna, D., Karreth, F. A., Rust, A. G., Perez-Mancera, P. A., Rashid, M., Iorio, F., Alifrangis, C., Arends, M. J., Bosenberg, M. W., Bollag, G., Tuveson, D. A., Adams, D. J. (2015) BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model. Proceedings of the National Academy of Sciences of the United States of America, 112 (6). E536-E545. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/25624498
DOI: 10.1073/pnas.1418163112

Abstract

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in approximately 80% of BRAFV600-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 BrafV618E (analogous to the human BRAFV600E 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 BrafV618E 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt
diseases & disorders > cancer
bioinformatics > genomics and proteomics
organism description > model organism
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date Deposited: 06 Feb 2015 19:47
Last Modified: 16 Oct 2015 14:49
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31184

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