Melanoma trial begins as new cancer drugs show promise

Moffitt Cancer Center researchers have discovered a novel mechanism that can lead melanoma cells to develop resistance to drugs that target the protein BRAF.

Mutations in the gene BRAF are the most common mutation found in melanoma, with up to 50 percent of tumors testing positive for the mutations.

Several agents that directly target BRAF have been approved by the Food and Drug Administration for the treatment of melanoma patients who have the mutation, including dabrafenib and vemurafenib. However, many patients become resistant to BRAF inhibitors and relapse. This resistance was associated with reactivation of the BRAF protein communication pathway in tumor cells.

Another gene that was frequently mutated in melanoma was PTEN. Studies have shown that melanoma patients who have both BRAF and PTEN mutations might have a poorer response to dabrafenib and vemurafenib therapy.

Moffitt researchers wanted to determine the mechanism responsible for resistance to BRAF inhibitors. They discovered that BRAF inhibitors cause BRAF and PTEN mutant melanoma cells to increase levels of fibronectin. Fibronectin is a protein that is expressed in the space surrounding cells.

The researchers found that higher levels of fibronectin allow melanoma cells to form their own protective environment that reduces the ability of BRAF inhibitors to kill tumor cells.

Importantly, the researchers discovered that melanoma patients who have PTEN mutations and higher levels of fibronectin in their tumors tend to have a lower overall survival. They also showed that targeting the tumor with BRAF inhibitors combined with a drug that targets the protective environment significantly enhances the killing effect of the BRAF inhibitor.

The researchers believe that effective cancer therapy in the future will require the combined action of drugs that target both the tumor and its adaptive responses to initial therapies. This was particularly important for melanoma patients because the survival of only a single cell after initial cancer therapy is enough to allow a melanoma tumor to regrow.

The study is published in the journal Oncogene.