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

Daniele Perna, Florian A. Karreth, Alistair G. Rust, Pedro A. Perez-Mancera, Mamunur Rashid, Francesco Iorio, Constantine Alifrangis, Mark J. Arends, Marcus W. Bosenberg, Gideon Bollag, David A. Tuveson, David J. Adams

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼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.
Original languageEnglish
Pages (from-to)E536-E545
JournalProceedings of the National Academy of Sciences (PNAS)
Volume112
Issue number6
Early online date26 Jan 2015
DOIs
Publication statusPublished - 10 Feb 2015

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