Researchers identify mechanism of resistance to BRAF inhibitors in melanoma

Melanoma is one of the most aggressive types of skin cancer, but recent advances in targeted therapies have improved the prognosis for many patients. Unfortunately, for some patients, these positive results do not last long, due to the emergence of drug resistance and tumor recurrence. Researchers at the Moffitt Cancer Center have discovered a mechanism by which melanoma cells become resistant to commonly used drugs that target the BRAF protein and its signaling pathway. Their study was published online today by the journal Research against cancer.

One of the most common genetic mutations in melanoma is the alteration of the BRAF gene. Mutations in BRAF occur in approximately 50% of melanomas, resulting in increased cell proliferation and survival. There are several drugs that target BRAF and a downstream gene called MEK that cooperates with BRAF in cancer development. These drugs have resulted in a significant improvement in outcomes for patients; However, many patients end up developing drug resistance.

Moffitt's researchers conducted a series of laboratory experiments with cell lines and mouse models to determine the resistance of melanoma to these commonly used drugs. They found that melanoma cells resistant to BRAF inhibitors experienced a response mechanism similar to cells treated with stressors, such as UV rays and low oxygen content. During each of these conditions, the cells increased the expression of the histone deacetylase 8 protein (HDAC8).

HDACs are proteins that regulate the level of expression and activity of other proteins in the cell. HDACs are often deregulated in cancer and several drugs targeting HDAC are approved for the treatment of different types of cancer. The researchers discovered that HDAC8 stimulated the activity of the transcription factor AP-1, which then increased the expression of genes involved in motility and cell invasion.

"Our work provides the first evidence that the activity of HDAC8 is increased in response to multiple cellular stresses, which initiates a transcription program badociated with increased survival of melanoma cells," explained Keiran Smalley, Ph. D., Director of the Donald A. Adams Center for Excellence in Melanoma and Skin Cancer at Moffitt.

This link between HDAC8 and drug resistance has suggested to researchers that drugs targeting HDACs may be able to overcome the mechanisms of cell resistance to BRAF inhibitors. The researchers performed a series of experiments on mice and found that concomitant treatment with HDAC and BRAF inhibitors better inhibited melanoma tumor growth than either agent alone.

The researchers hope their work will lead to clinical studies that will examine the potential of HDAC inhibitors to prevent the development of drug resistance in melanoma. "These results provide a strong rationale for further development of more selective and potent HDAC8 inhibitors for future evaluation as drugs that can limit phenotype changes and therapeutic leaks in melanoma." "said Smalley.