How Does Melanoma Become Resistant to Targeted Therapy?

Discovery may lead to new treatment designs.

Researchers have discovered a process through which melanoma becomes resistant to a particular form of targeted therapy, which may generate a new disease target or new treatment designs, a recent study indicates.

The study, published in Clinical Cancer Research, focused on the BRAFV600E/K gene, which is mutated in approximately 40 to 50% of all melanoma cases. Patients with the mutation who receive drugs that target BRAF mutations have been found to have a slightly longer survival rate, however they frequently relapse within several months of treatment.

"We once 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," lead author Russel E. Kaufman, MD, said in a press release. "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."

The researchers targeted macrophages, which are the most abundant inflammatory cell in melanomas. An inverse correlation has been found between the presence of macrophages and patient outcome at all stages of the disease, the study noted.

The researchers examined melanoma cells and macrophages through an in vitro cell co-culture system and several analytic procedures to evaluate cancer proliferation levels and cell death. The study also utilized 2 preclinical models of mice to find out if targeting macrophages can increase the effectiveness of BRAF inhibitors.

The study found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in macrophages, which is used to aid receptors on the cell surface to communicate with DNA inside of the cell to produce proteins.

Activation of the pathway causes production of vascular endothelial growth factor (VEGF), which promotes blood vessel formation that tumors need to survive. As a result, the production of VEGF in macrophages activates the MAPK pathway in melanoma cells to stimulate cancer cell growth.

The researchers found that blocking the MAPK pathway or VEGF signaling apparently reverses macrophage-mediated resistance. Additionally, targeting macrophages raised the antitumor activity of BRAF inhibitors in both mouse and human tumor models.

The presence of macrophages in melanomas also predicted earlier relapse following treatment.

"This study gives us important insight into the off-target effects these inhibitors can have on patients," Kaufman said. "With this piece of information, we have determined just how important one of these off-target effects can be, and from here, we can decide whether the right approach is to target the macrophages themselves or to design new BRAF-inhibiting drugs that do not activate macrophages."