The Role of p53R248W in Melanoma

Melanoma is the deadliest form of skin cancer. Most melanomas are associated with UltraViolet Radiation (UVR) exposure, which induces the BRAFV600E mutation in melanocytes which give rise to melanoma. BRAFV600E occurs in ~50% of melanomas and constitutively stimulates mitogen-activated protein kinase signaling promoting abnormal cell proliferation. UVR also mutates the tumor suppressor p53 that prevents malignancy by triggering apoptosis in damaged skin cells. p53R248W, a UVR signature mutation, is the most common p53 mutation in skin cancers. Recent findings show that BRAFV600E cooperates with p53 alterations to grow aggressive melanomas. For the first time, we explore the role of p53R248W in the initiation and progression of melanoma using transgenic BRAFV600E mice with and without p53 or p53R245W (human p53R248W). Preliminary findings show that p53R245W synergizes with BRAFV600E to initiate melanomagenesis and increases the rate of skin tumor proliferation. An understanding of how UVR signature p53 mutations impact melanoma will inform the development of novel therapeutic strategies that target metastatic melanoma that is resistant to most conventional therapies.