Summary Metastases are the major cause of melanoma-related mortality. Previous studies implicating aberrant AKT signaling in human melanoma metastases led us to evaluate the effect of activated AKT1 expression in non-metastatic BRAFV600E/Cdkn2aNull mouse melanomas in vivo. Expression of activated AKT1 resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of our mice, respectively. Interestingly, silencing of PTEN in BRAFV600E/Cdkn2aNull melanomas cooperated with activated AKT1 resulting in decreased tumor latency and the development of lung and brain metastases in nearly 80% of tumor-bearing mice. These data demonstrate that AKT1 activation is sufficient to elicit lung and brain metastases in this context and reveal that activation of AKT1 is distinct from PTEN silencing in metastatic melanoma progression. These findings advance our knowledge of the mechanisms driving melanoma metastasis and may provide valuable insights for clinical management of this disease.

Dysregulated protein kinase B alpha (PKB/AKT1) signaling has been increasingly implicated in melanoma metastasis to distant organs, especially the brain. In a recent study, we expressed activated AKT1 in a non-metastatic melanoma model in vivo and discovered that AKT1 activation decreased tumor latency and elicited lung and brain metastases in this context.

Brain metastases are a major cause of melanoma-related mortality and morbidity. The molecular mechanisms driving melanoma to 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 metastasis is the lack of an in vivo model that faithfully mimics the human disease. Based on previous studies implicating aberrant AKT signaling in human melanoma brain metastases, we evaluated the effect of activated AKT1 expression in non-metastatic BRAFV600E/INK4A-ARFNull mouse melanomas in vivo. Expression of activated AKT1 in this context resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of our mice, respectively. Surprisingly, silencing of PTEN in BRAFV600E/INK4A-ARFNull melanomas did not yield a statistically significant metastatic phenotype but in combination with activated AKT1 resulted 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 BRAFV600E/INK4A-ARFNull mouse melanomas expressing activated AKT1 relative to PTEN-null counterparts. This study advances the field of melanoma brain metastasis by (1) providing the first in vivo, autochthonous model of melanoma with spontaneous metastasis to the lungs and brain, (2) demonstrating that expression of activated AKT1 is sufficient to elicit brain metastasis in BRAFV600E/INK4A-ARFNull mouse melanomas and (3) revealing distinct differences and cooperation between AKT1 activation and PTEN silencing in metastatic melanoma progression. In summary, this work advances our knowledge of the mechanisms driving melanoma brain metastasis and may provide valuable insights for the clinical management of this disease. Citation Format: David Kircher, Joseph Cho, James Robinson, Rowan Arave, Russell Green, Guo Chen, Michael Davies, Allie Grossmann, Matthew VanBrocklin, Martin McMahon, Sheri Holmen. AKT1 activation promotes brain metastasis in a mouse model of melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: 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.