Abstract B07: Differential roles for AKT isoforms in BRAF mutant melanoma

Despite recent advances, melanoma remains the deadliest form of skin cancer, and new therapeutic strategies are urgently needed. The MAP kinase (MAPK) and PI3K/AKT pathways are central to both disease progression and chemoresistance in melanoma, with dual targeting approaches yielding promising results that would benefit from increased target specificity and selectivity. The AKT family of serine/threonine kinases comprises three highly homologous and functionally distinct isoforms (AKT1, AKT2, and AKT3) that play unique roles in melanoma but have not yet been leveraged for isoform-specific targeting.

Our lab has engineered a unique mouse model of melanoma, in which mutant BRAFV600E is constitutively targeted to mouse melanocytes, resulting in spontaneous malignant disease upon additional loss of tumor suppressor genes, and faithfully recapitulates the human disease. We have identified differential and dynamic activation of AKT isoforms in our mouse melanoma model, which supports the hypothesis that AKT isoforms may play both non-redundant and compensatory roles in melanoma progression. To systematically address this question, we have genetically ablated each AKT isoform individually in melanoma-prone mice in order to elucidate the individual and unique contribution of each isoform to melanoma progression.

In parallel, we performed in vitro studies using shRNA mediated conditional knockdown of AKTs in a wide variety of human melanoma cell lines. Our results support an isoform-specific role for AKT1 in promoting melanoma cell proliferation, while AKT2 stimulates cell migration. Further studies utilizing the precision genome editing technology CRISPR/Cas9 allows us to interrogate the effects of AKT isoform specific knockout (KO) on in vivo tumor formation. This work moves toward establishing the contribution of AKT isoforms to tumor progression in melanoma, using both human melanoma cell lines and mouse models, to advance our understanding of the role of AKT in melanomagenesis. With AKT inhibitors in clinical trials for melanoma, our findings could yield novel therapeutic strategies and increase the efficiency of existing therapies to improve treatment options and outcome for this devastating disease.

Citation Format: Siobhan K. McRee, Jodie R. Pietruska, Elisabeth Dignan, Philip W. Hinds. Differential roles for AKT isoforms in BRAF mutant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B07.