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Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma

Marsh Durban, Victoria, Deuker, Marian M., Bosenberg, Marcus W., Phillips, Wayne and McMahon, Martin 2013. Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. The Journal of Clinical Investigation 123 (12) , pp. 5104-5118. 10.1172/JCI69619

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Abstract

Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway–targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway–targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Last Modified: 01 Feb 2017 04:51
URI: http://orca.cf.ac.uk/id/eprint/66267

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