The study investigates the role of BRAFV600E and Pten silencing in the development of metastatic melanoma in mice. Mice with conditional expression of BRAFV600E in melanocytes developed benign melanocytic hyperplasias that did not progress to melanoma. However, when combined with Pten silencing, these mice developed melanoma with 100% penetrance, short latency, and metastases to lymph nodes and lungs. Inhibitors of mTORC1 (Rapamycin) and MEK1/2 (PD325901) prevented melanoma but failed to eliminate it upon drug cessation, indicating the presence of long-lived melanoma-initiating cells. Combined treatment with Rapamycin and PD325901 led to shrinkage of established melanomas. These mice, with a genetic profile similar to human melanoma, provide a valuable model for studying melanoma metastasis and pre-clinical evaluation of therapeutic agents. The study highlights the cooperative role of BRAFV600E and Pten silencing in melanoma initiation and progression, and demonstrates the effectiveness of targeting these pathways in preventing and treating melanoma. The model also shows that melanoma can recur even after treatment, suggesting the need for combination therapies. The findings have implications for the development of new therapeutic strategies for melanoma.The study investigates the role of BRAFV600E and Pten silencing in the development of metastatic melanoma in mice. Mice with conditional expression of BRAFV600E in melanocytes developed benign melanocytic hyperplasias that did not progress to melanoma. However, when combined with Pten silencing, these mice developed melanoma with 100% penetrance, short latency, and metastases to lymph nodes and lungs. Inhibitors of mTORC1 (Rapamycin) and MEK1/2 (PD325901) prevented melanoma but failed to eliminate it upon drug cessation, indicating the presence of long-lived melanoma-initiating cells. Combined treatment with Rapamycin and PD325901 led to shrinkage of established melanomas. These mice, with a genetic profile similar to human melanoma, provide a valuable model for studying melanoma metastasis and pre-clinical evaluation of therapeutic agents. The study highlights the cooperative role of BRAFV600E and Pten silencing in melanoma initiation and progression, and demonstrates the effectiveness of targeting these pathways in preventing and treating melanoma. The model also shows that melanoma can recur even after treatment, suggesting the need for combination therapies. The findings have implications for the development of new therapeutic strategies for melanoma.