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

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 activa...

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Bibliographic Details
Published in:The Journal of clinical investigation 2013-12, Vol.123 (12), p.5104-5118
Main Authors: Marsh Durban, Victoria, Deuker, Marian M, Bosenberg, Marcus W, Phillips, Wayne, McMahon, Martin
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Class I Phosphatidylinositol 3-Kinases
Enzyme Activation - genetics
Female
Humans
Male
Melanoma - pathology
Melanoma, Experimental - enzymology
Melanoma, Experimental - etiology
Melanoma, Experimental - pathology
Mice
Mutation
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - genetics
Neoplasm Proteins - physiology
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - physiology
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Protein Processing, Post-Translational
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - physiology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - physiology
PTEN Phosphohydrolase - deficiency
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - physiology
Signal Transduction
Specific Pathogen-Free Organisms
Tumor Cells, Cultured
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI69619