In a new study entitled “BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth,” researchers suggest that a specific type of immune cell — macrophages — offers a potential new therapeutic target in patients with melanoma resistance to BRAF inhibitors. The study was published in the journal Clinical Cancer Research.
Melanoma patients harbor (in 40 to 50% of the cases) mutations in the BRAFV600E/K gene. Patients with advanced BRAF mutant melanomas are treated with standard targeted BRAF inhibitors (e.g., vemurafenib or dabrafenib). However, while treatment increases patients’ survival, relapse ultimately occurs after months of treatment.
In this study, the authors wanted to understand the cause for melanoma resistance to BRAF inhibitors, focusing on macrophages due to their high abundance in melanomas (macrophages are the prominent type of inflammatory cells found in these tumors). Nonetheless, macrophages’ role in tumor resistance to anticancer treatments, namely BRAF inhibitors, remains unknown.
The team performed in vitro studies (with macrophages and melanoma cells’ co-culture systems) and discovered that BRAF inhibitors activate a pathway in macrophages, the mitogen-activated protein kinase (MAPK), leading to the production of vascular endothelial growth factor (VEGF). This enhanced tumor growth by inducing the formation of new blood vessels (a process known as angiogenesis). Additionally, VEGF released by macrophages activated the MAPK pathway in melanoma cells, stimulating cancer proliferation.
The authors discovered that blocking the MAPK pathway or VEGF signaling was an effective strategy to reverse macrophage-mediated resistance. When combining BRAF inhibitors with targeted macrophage therapy the team found that the anti-tumor activity of BRAF inhibitors, tested in both mouse and human tumor models, was significantly increased.
The team highlighted that their results demonstrate, that while macrophage infiltration in melanoma is a sign for relapse after treatment and a plays a key role in melanoma resistance to BRAF inhibitors, therapeutic strategies targeting macrophages will surely improve patient outcomes.
Russel E. Kaufman, M.D., president emeritus of The Wistar Institute and study lead author commented in a press release, “This study gives us important insight into the off-target effects these inhibitors can have on patients. 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.”