Melanomagenesis is a multistep process involving various cellular and molecular changes. The phospho-inositide-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways have important roles in melanoma development. Treatment with BRAF inhibitors can be highly effective against metastatic melanomas, but the effects are limited to BRAFV600E patients, and resistance often develops. PTEN and NRAS, both major components of the PI3K and MAPK pathways, are potential alternative targets for melanoma therapy. The aim of this study was to evaluate the cooperation between NRAS and PTEN during melanomagenesis. PTEN expression is frequently altered in melanoma, but the role of PTEN is not yet fully understood. We found concomitant NRAS mutation and loss of PTEN in human melanoma samples and cell lines. Then, we studied transgenic mice with inactivation of PTEN and/or expression of an oncogenic form of NRAS in the melanocyte lineage. PTEN inactivation alone had no discernible effect on melanomagenesis. However, in melanomas initiated by oncogenic NRAS, inactivation of PTEN caused more rapid melanoma development and higher metastatic rate. We demonstrate that PTEN loss induces a senescence bypass. Thus, PTEN inactivation cooperated with oncogenic NRAS to promote melanoma initiation and progression
