Melanoma: Targeting Macrophages Increases BRAF Inhibitors’ Effectiveness

Russel E. Kaufman, MD President Emeritus Professor, Molecular and Cellular Oncogenesis Program Molecular and Cellular Oncogenesis Program The Wistar InstituteMedicalResearch.com Interview with:
Russel E. Kaufman, MD President Emeritus
Professor, Molecular and Cellular Oncogenesis Program
Molecular and Cellular Oncogenesis Program
The Wistar Institute

Medical Research: What is the background for this study? What are the main findings?

Response: Targeted therapies in cancer were hailed as a “magic bullet” because of their ability to act upon the mutations responsible for cancer while leaving nearby healthy cells alone. Using an approach like this, it would make sense that therapies designed to target mutations of BRAFV600E/K could be effective for melanoma, since that gene is mutated in about half of all cases of the disease.

However, we’ve learned over time that these targeted therapies simply aren’t as effective as we had hoped they would be. In the case of these BRAF inhibitors, while patients do live slightly longer, they eventually relapse within months of treatment. We wanted to know why this was happening.

We decided to look at macrophages, which are the most abundant inflammatory cells in melanoma. The more macrophages present in a patient with melanoma, the worse his or her outcome will be. They’ve been linked to cancer progression, but before this study, no one had really looked at the role they may play in the resistance to treatment with BRAF inhibitors.

We found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in macrophages. When this pathway is activated, it leads to the production of vascular endothelial growth factor (VEGF), a signaling protein closely associated with angiogenesis. The VEGF produced in the macrophages is able to activate the MAPK pathway in melanoma cells, thereby stimulating the growth of cancer cells.

Taking these findings one step further, we discovered that when we blocked the MAPK pathway or VEGF signaling, we appeared to reverse macrophage-mediated resistance. When we targeted macrophages, we were able to increase the antitumor activity of BRAF inhibitors in mouse and human models.

Medical Research: What should clinicians and patients take away from your report?

Response: This is just one explanation for how patients who are treated with BRAF inhibitors eventually become resistant to the targeted therapy. We believed that focusing on macrophages would provide us with a reasonable explanation for why this is happening, and it did, but there are many, many off-target effects caused by targeted therapies that we don’t yet understand. There really needs to be a comprehensive study that explores all of the different ways in which targeted therapies can affect a patient or cause different cancer-causing pathways to become activated.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: It’s possible that therapy can be improved by targeting the macrophages themselves, since this stimulated the antitumor activity of BRAF inhibitors. However, since macrophages are the culprit behind this one form of BRAF inhibitor resistance, we might also want to consider designing new BRAF inhibitors that do not activate macrophages.

Citation:

BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth

Tao Wang, Min Xiao, Yingbin Ge, Clemens Krepler, Eric Belser, Alfonso Lopez-Coral, Xaiowei Xu, Gao Zhang, Rikka Azuma, Qin Liu, Rui Liu, Ling Li, Ravi K Amaravadi, Wei Xu, Giorgos C Karakousis, Tara C Gangadhar, Lynn M. Schuchter, Melissa Lieu, Sanika Khare, Molly B Halloran, Meenhard Herlyn, and Russel E. Kaufman

Clin Cancer Res clincanres.1554.2014; Published Online First January 23, 2015; doi:10.1158/1078-0432.CCR-14-1554

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MedicalResearch.com Interview with: Russel E. Kaufman, MD (2015). Melanoma: Targeting Macrophages Increases BRAF Inhibitors’ Effectiveness 

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