BRAF Inhibitors Used in Melanoma Treatment Stimulate Tumor to Increase Production of Fibronectin; This Protects the Tumor and Leads to Drug Resistance; Study Suggests This Protective Environment Should Also Be Targeted

The development of targeted therapies has significantly improved the survival of melanoma patients over the last decade; however, patients often relapse because many therapies do not kill all of the tumor cells, and the remaining cells adapt to treatment and become resistant. Moffitt Cancer Center researchers in Tampa, Florida have discovered a novel mechanism that can lead melanoma cells to develop resistance to drugs that target the protein BRAF (image). The article was published online on June 15, 2015 in Oncotarget. Mutations in the BRAF gene are the most common mutation found in melanoma, with up to 50 percent of tumors testing positive for such mutations. Several agents that directly target BRAF have been approved by the Food and Drug Administration for the treatment of melanoma patients who have a BRAF mutation. These agents include dabrafenib and vemurafenib. However, many patients become resistant to BRAF inhibitors and relapse. This resistance is associated with reactivation of the BRAF protein communication pathway in tumor cells. Another gene that is frequently mutated in melanoma is PTEN. Studies have shown that melanoma patients who have both BRAF and PTEN mutations may 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.