1. BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.
- Author
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Perna D, Karreth FA, Rust AG, Perez-Mancera PA, Rashid M, Iorio F, Alifrangis C, Arends MJ, Bosenberg MW, Bollag G, Tuveson DA, and Adams DJ
- Subjects
- Animals, Animals, Genetically Modified, Blotting, Southern, Blotting, Western, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Embryonic Stem Cells metabolism, Exome genetics, Genetic Association Studies, Hepatocyte Growth Factor metabolism, Humans, Immunohistochemistry, Indoles pharmacology, Melanoma metabolism, Mice, Mutagenesis, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Signal Transduction genetics, Sulfonamides pharmacology, Transposases metabolism, bcl-Associated Death Protein metabolism, Drug Resistance, Neoplasm physiology, Melanoma drug therapy, Oncogene Protein p21(ras) metabolism, Proto-Oncogene Proteins B-raf metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction physiology
- 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.
- Published
- 2015
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