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Macrophages May Play Critical Role in Melanoma Resistance to BRAF Inhibitors

Surprising findings from a study performed by researchers at The Wistar Institute may change the way medications are designed to treat melanoma.

For years, targeted therapies have been used in the treatment of melanoma, however, researchers from The Wistar Institute have discovered that melanoma may be resistant to targeted therapies leading to a new melanoma target or prompting new designs of these treatments.

Targeted therapies were designed to target the mutations responsible for cancer while sparing healthy, unmutated cells. Since BRAF is mutated in 40-50 percent of all cases of melanoma, this seemed to be the promising target. Patients treated with BRAF inhibitors do live slightly longer; however, they often relapse within several months of treatment.

“Once we thought targeted therapies could be a ‘magic bullet’ for cancer treatment, but we’ve learned over time that this simply is not the case, especially with regard to BRAF inhibitors for melanoma,” said Russel E. Kaufman, M.D., president emeritus of The Wistar Institute and lead author of the study. “We felt it was important to examine the tumor microenvironment to provide one possible explanation for why patients become resistant to targeted therapy in order to guide treatment decisions and perhaps arrive at better, more effective therapies.”

Kaufman focused this study on macrophages, which are the most abundant inflammatory cell in melanoma, and their presence is inversely correlated with patient outcomes at all stages of the disease. Researchers discovered that blocking specific pathways appeared to reverse macrophage-mediated resistance. Targeting macrophages also increased the antitumor activity of BRAF inhibitors in mouse and human tumor models. The presence of macrophages in melanomas was able to predict earlier relapse after treatment.

With the new information gathered from this study, we have new insight on the treatment of melanoma. Whether the right approach is to target the macrophages themselves or to design new BRAF-inhibiting drugs that do not activate macrophages is to be determined.

By: Gina C. Bird, MPAS, PA-C, SDPA Conference Co-Chair

Adapted from original press release by Ben Leach at bleach@wistar.org

[image by University of Liverpool]