Study Identifies Key Mechanism Involved in Promoting Melanoma Proliferation
Researchers have identified a microRNA, miR-146a, that accelerates in the presence of BRAF and NRAS genetic mutations—which occur in 70% of melanoma cases—by activating the Notch signaling pathway. The finding could provide a new drug development target for patients with melanoma. The study by Forloni et al is published in eLife.
Study Findings
The researchers analyzed melanoma cell lines and matched patient samples looking at all the microRNAs present in cells carrying a mutated form of either BRAF or NRAS, and compared them with the microRNAs found in healthy cells. They found that miR-146a was much more common in the cancer cells. In addition, production of this microRNA was increased by the two cancer-causing mutations. The researchers found that increasing production of miR-146a caused the melanoma cells to grow faster, and also caused tumors to develop in mice, while reducing miR-146a levels had the opposite effect.
The researchers also looked at cancer cells taken from patients at various stages of their skin cancer and found that, as the disease progresses, an unprocessed form of miR-146a tends to acquire a mutation, which leads to much higher levels of the active, processed form of the microRNA in the cancer cells. High levels of miR-146a also switched off a gene that encodes for a protein that, in turn, switches off a protein called Notch that is linked to skin cancer, showing that excess miR-146a actually increases the activation of the Notch protein.
Possible Therapeutic Targets
The study findings suggest that blocking the Notch signaling pathway as well as the MAP kinase pathway, which is also activated by BRAF and NRAS, represent a valuable drug development target. “Our results suggest that combining clinically approved γ-secretase inhibitors, which block Notch activation, with BRAF inhibitors, which block BRAF-MEK-ERK signaling, might be a more effective treatment of BRAF/NRAS mutant melanomas,” wrote the researchers.
Michael R. Green, MD, PhD, of University of Massachusetts Medical School, and Narendra Wajapeyee, PhD, of Yale University School of Medicine, are the corresponding authors for the eLife article.
The study was supported by grants from the Melanoma Research Alliance, Melanoma Research Foundation, Howard Hughes Institute, and the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
