Malignant melanoma is the deadliest form of skin cancer, and if not treated successfully, it can spread to affect the liver, lungs, or brain. Chemotherapy fights the disease with limited efficiency, and the use of interferon has become the most established immunotherapy for advanced-stage melanoma. However, melanoma tumors often develop a resistance to the drug, posing one of the major obstacles in the clinical treatment of this cancer.
Now Professor Manfred Schartl and Dr. Claudia Wellbrock, scientists at the University of Würzburg, believe they have an explanation for how this interferon resistance is acquired. They have found that when a gene called STAT5 is too active in melanoma cells, it can counteract the anti-cancer effect of interferon. Interferon normally impedes the growth of cancer cells, whereas STAT5 is thought to act to promote cellular growth.
The new work, published by Professor Schartl and his colleagues in Current Biology, shows that interferon actually activates STAT5 in melanoma cells but that under normal conditions, this does not interfere with the inhibitory potential of the drug. However, when cancer cells posses too much STAT5 activity to begin with, the further activation of STAT5 function by interferon induces a mechanism that blocks the ability of the drug to effectively inhibit growth.
Confirming this initial finding, the researchers found that when they inhibited STAT5 in interferon-resistant melanoma cells, they were able to restore the effectiveness of interferon. This demonstrates the relevance of STAT5 and its contribution to the behavior of melanoma cells in the late stage of the disease.
The findings explain the frequent failure of interferon therapies and thus further our understanding of melanoma in its late, and most aggressive, stage. In the future, a routine analysis of the STAT5 status in melanoma patients might help to improve and personalize therapies.
The researchers include Claudia Wellbrock of the University of Würzburg in Würzburg, Germany, and the Institute of Cancer Research in London, United Kingdom; Christin Weisser, Jessica C. Hassel, Petra Fischer, Manfred Schartl, Jürgen Becker and Claudia S. Vetter of the University of Würzburg in Würzburg, Germany; Iris Behrmann, Marcin Kortylewski and Peter C. Heinrich of Rheinisch-Westfälische Technische Hochschule in Aachen, Germany. This work was supported by the Deutsche Forschungsgemeinschaft, the European Union (EU) and by the Graduiertenkolleg "Regulation des Zellwachstums."
Wellbrock et al.: "STAT5 contributes to interferon resistance of melanoma cells." Publishing in Current Biology, Vol. 15, 1629–1639, September 20, 2005, DOI 10.1016/j.cub.2005.08.036 www.current-biology.com.
Journal
Current Biology