A gene identified in some melanoma appears to make the tumor cells more resistant to treatment. The gene TP63 is unexpectedly expressed in some melanoma tumors and correlates significantly with a worse prognosis. Researchers hope this new understanding of what makes some melanoma cells so difficult to kill will help develop new therapies.

Melanoma is a form of skin cancer that usually appears on the body as a new or changing mole. While it is less common than other forms of skin cancer—approximately 5% of skin cancers are melanoma—approximately 75% of skin cancer-related deaths are associated with melanoma. The number of melanoma cases is rising faster than almost any other cancer. One of the main factors is ultraviolet light from the sun or tanning beds. Early-stage melanomas can often be removed by surgery, whereas more advanced melanomas are much harder to treat.

“For most patients where the melanoma has spread beyond the skin, there are few effective treatments and overall survival rates for this disease have not changed much over the past 30 years.  To develop better treatments we need to understand the basic biology underpinning why these cells are so resistant to being killed,” said Daniele Bergamaschi, PhD, of Queen Mary, University of London.

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The researchers analyzed 156 melanoma tissue samples from 129 patients for expression of the protein p63—the protein encoded by the gene TP63. They found that p63 was expressed in more than 50% of the samples (58% of primary metastatic samples, 53% of recurrent samples, and 66% of metastatic samples) and correlated significantly with death from melanoma. This research was published in the Journal of Experimental Medicine (2013; doi:10.1084/jem.20121439).

Bergamaschi said, “We did not expect to find the TP63 gene expressed in melanoma. It is not usually found in the melanocytes (skin pigment cells), which are the cells from which melanomas develop. However, it appears in some cases this gene is turned on as the tumor forms, and when it does it is linked to a worse prognosis.”

The researchers suggest that the TP63 gene, and the subsequent production of the protein p63 in some melanoma, is inhibiting the apoptotic function of the protein p53. One of the main activities mediated by p53 is apoptosis.

“The apoptotic pathway is often not working in melanoma. However this is not explained by mutations in the TP53 gene, which encodes for the p53 protein, as evidence suggests this is mutated in less than 10% of melanoma,” said Bergamaschi. “This work suggests that in a significant number of cases it is actually the protein p63 which is inhibiting p53’s apoptotic function, making some tumors more resistant to treatment. We therefore suggest that p63 should be considered when designing new treatments for melanoma which are focused on reactivating the apoptotic pathway in order to make the cancer cells easier to kill.”