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 activation of the gene encoding the catalytic subunit of PI3K alpha (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 BRAF(v600E) -induced. melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway-targeted inhibitors. These experiments revealed that mutationally activated PIK3 CAI-11 47R cooperates with BRAF(v600E) for melanomagenesis in mice. Moreover, pharmacological inhibition of P13 Ks prevented growth of BRAF(v600E)/PTENN1Lll melanomas in vivo and in tissue culture. Combined inhibition of BRAF(v600E) and PI3K had more potent effects on the regression of established BRAFvooEipTENNuu melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAF vsoovpiK3 cAxi wit melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFv6 E/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 BRAF(v600E) and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway-targeted inhibition of PI3K and BRAF(v600E) in the therapeutic management of BRAF(v600E)/PTENNull melanomas.