Trametinib May Play a Dual Role in Merkel Cell Carcinoma

Trametinib (Mekinist), which is approved by the US Food and Drug Administration (FDA) for melanoma and other cancers, may block viral infection by stopping Merkel cell polyomavirus transcription and replication, according to a new study published in Cell Host & Microbe. The researchers reported that low doses of trametinib wiped out viral infection in a cell culture model.

In addition, the researchers found that normal control cells were not affected by treatment with trametinib. The researchers say this suggests that trametinib might be able to be used with few side effects for reducing the viral load in immunocompromised patients. It is hoped that this agent or one similar to it may have a role in preventing the development of Merkel cell carcinoma.

“We established a cell culture model for Merkel cell polyomavirus infection, which will help us find how this DNA virus causes cancer,” said senior author Jianxin You, PhD, an associate professor of Microbiology at the University of Pennsylvania, Philadelphia, in a Penn Medicine news release.

Merkel cell polyomavirus infection can lead to Merkel cell carcinoma in immune-compromised individuals. These findings open the door to a new way to investigate this type of oncogenic viral infection and they help identify potential therapeutic agents against Merkel cell polyomavirus infection.  Merkel cell polyomavirus preferentially infects dermal fibroblasts in human skin. Merkel cell carcinoma, which metastasizes rapidly, has a mortality rate of 33%. The 5-year survival rate is 45%. 

Due to the huge unmet clinical need, there has been keen interest in better understanding the etiology of Merkel cell carcinoma and how best to prevent it. The researchers have discovered that the activation of enzymes known as matrix metalloproteinases (MMPs), by a cellular signaling pathway involving the WNT and b-catenin proteins, stimulate Merkel cell polyomavirus infection.

The Merkel cell polyomavirus is commonly found on healthy human skin. Excessive exposure to sunlight and ultraviolet radiation, immune suppression, and advanced age are the most important risk factors for Merkel cell carcinoma. Although the exact function of Merkel cells, found in the lower part of the epidermis, is unknown, it is thought that nerve-associated cells from light touch sensation may be involved.

The researchers hope next to establish an animal model to elucidate the mechanisms by which Merkel cell polyomavirus infection leads to Merkel cell carcinoma. This work built on the system for production of both Merkel cell polyomavirus pseudovirus and recombinant virions established in the laboratory of Christopher Buck, PhD, at the National Cancer Institute (NCI).