Mutant BRAF and AKT cooperate to induce melanoma formation

Genetic studies have greatly advanced our understanding of the molecular and genetic drivers underlying the steps of melanomagenesis. Although activation of the mitogen-activated protein kinase (MAPK) signaling pathway-specifically in the form of a single driver mutation in the oncogenes BRAF or NRAS-triggers melanocyte proliferation in over 60% of cases, mutations in the RAS pathway alone are not sufficient for melanoma formation. However, the addition of activating tumorigenic mutations or loss of tumor suppressor functions in the phosphoinositide 3-kinase (PI3K) pathway promotes the escape from oncogene-induced senescence, leading to the formation of malignant melanomas. While dysregulation of the PI3K lipid signaling cascade in melanoma is conventionally believed to occur through activation of AKT, it has not been shown whether constitutively active AKT can substitute for mutationally activated PI3K or loss of PTEN in mutant BRAF melanomagenesis in the absence of Cdkn2a loss.In this study, we investigated the potential of aberrant MAPK signaling through mutational activation of BRAF to cooperate with dysregulated AKT signaling to drive melanoma tumor formation and observed that genetic alterations in both BRAF and Akt1 are sufficient to promote melanomagenesis. Using an established autochthonous melanoma mouse model, we evaluated the ability of constitutively active Akt1 to promote tumor initiation and progression and found that Akt1 was sufficient to initiate tumorigenesis with an average tumor onset of 130.5 ± 32.5 days and a median overall survival of 178 ± 2.70 days. We have previously established the potential of myrAkt1 to enhance tumor activity and metastasis with additional genetic events such as loss of the tumor suppressors Pten and Cdkn2a. We now demonstrate that Akt1 not only drives melanoma progression and promotes metastasis but also plays a role in melanoma initiation. Furthermore, proteomic analysis of tumors using reverse-phase protein array (RPPA) revealed an upregulation of total FAK protein in the Pten samples, a finding that we are currently investigating further. Results from this study establish a role for Akt1 in melanoma initiation and highlight the ability of multiple alterations in the PI3K/AKT signaling pathway to influence BRAF mutant melanoma initiation, progression, and metastasis.