Abstract 37: AKT1 activation promotes brain metastasis in a mouse model of melanoma

Brain metastases are a major cause of melanoma-related mortality and morbidity. The molecular mechanisms driving melanomato the brain remain largely unclear, adding to the difficulties in both treating and prognosticating risk for this disease complication. One of the great barriers impeding the study of melanoma brain metastasisis the lack of an in vivo model that faithfully mimics the human disease. Based on previous studies implicating aberrant AKT signaling in human melanomabrain metastases, we evaluated the effect of activated AKT1expression in non-metastatic BRAF V600E/INK4A-ARF Null mouse melanomasin vivo . Expression of activated AKT1in this context resulted in highly metastatic melanomaswith lung and brain metastases in 67% and 17% of our mice, respectively. Surprisingly, silencing of PTENin BRAF V600E/INK4A-ARF Null melanomasdid not yield a statistically significant metastatic phenotype but in combination with activated AKT1resulted in decreased tumor latency and development of brain metastases in nearly 80% of tumor-bearing mice. Furthermore, we found evidence of increased mTOR signaling in BRAF V600E/INK4A-ARF Null mouse melanomasexpressing activated AKT1relative to PTEN-null counterparts. This study advances the field of melanoma brain metastasisby (1) providing the first in vivo, autochthonous model of melanomawith spontaneous metastasis to the lungs and brain, (2) demonstrating that expression of activated AKT1is sufficient to elicit brain metastasisin BRAF V600E/INK4A-ARF Null mouse melanomasand (3) revealing distinct differences and cooperation between AKT1activation and PTENsilencing in metastatic melanomaprogression. In summary, this work advances our knowledge of the mechanisms driving melanoma brain metastasisand may provide valuable insights for the clinical management of this disease. Citation Format: David Kircher, Joseph Cho, James Robinson, RowanArave, Russell Green, Guo Chen, Michael Davies, Allie Grossmann, Matthew VanBrocklin, Martin McMahon, Sheri Holmen. AKT1activation promotes brain metastasisin a mouse model of melanoma. [abstract]. In: Proceedings of the AACR Precision MedicineSeries: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 37.