Differential AKT dependency displayed by mouse models of BRAF ^V600E-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 PTEN^Null 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 BRAF^V600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway-targeted inhibitors. These experiments revealed that mutationally activated PIK3CA^H1047R cooperates with BRAF^V600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAF^V600E/ PTEN^Null melanomas in vivo and in tissue culture. Combined inhibition of BRAF^V600E and PI3K had more potent effects on the regression of established BRAF^V600E/PTEN^Null melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAF^V600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAF ^V600E/PTEN^Null 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/PTEN ^Null melanomas.