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

2015; National Academy of Sciences; Volume: 112; Issue: 6 Linguagem: Inglês

10.1073/pnas.1418163112

1091-6490

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

Protein Degradation and Inhibitors

Significance Using Sleeping Beauty transposon mutagenesis in a melanoma model driven by oncogenic BRAF (B-Raf proto-oncogene, serine/threonine kinase), we identified both known and novel candidate genes that mediate resistance to the BRAF inhibitor PLX4720. We validate ES-cell expressed Ras as a novel promoter of BRAF inhibitor resistance and propose that AKT (v-akt murine thymoma viral oncogene homolog 1)-mediated inactivation of BAD (BCL2-associated agonist of cell death) constitutes a pathway that may contribute to hepatocyte growth factor-mediated therapy resistance. Our work establishes Sleeping Beauty mutagenesis as a powerful tool for the identification of novel resistance genes and mechanisms in genetically modified mouse models.