Defective Jak-STAT signal transduction pathway in melanoma cells resistantto growth inhibition by interferon-alpha

Advanced malignant melanoma is an aggressive malignancy with poor prognosis . Current therapeutic strategies have a modest success rate. The most promi sing treatment consists of a combination of chemotherapy with interferon-al pha, but complete response rates remain less than 15%. interferon-alpha is also effective in adjuvant therapy for non-advanced melanoma treated surgic ally. The molecular mechanisms leading to loss of growth restraints and gai n of growth-promoting functions during carcinogenesis of malignant melanoma are not understood in detail. Here, we studied 9 human melanoma cell lines with regard to growth inhibition by interferon-alpha and defects in intrac ellular signal transduction through the lak-STAT pathway. In 3 cell lines, we found a complete loss of growth restraint by interferon-alpha. In all of them, different components of the lak-STAT pathway were defective. Since s ignal transduction through the lak-STAT pathway is necessary for antiviral and antiproliferative effects of interferons, we conclude that defects in t his pathway may be one of the mechanisms that lead to cancer progression th rough loss of growth-restraining functions. Moreover, our results indicate that a subgroup of melanomas could be completely resistant to interferon-al pha and should therefore not be treated with this cytokine, (C) 2000 Wiley- Liss, Inc.