Cross resistance of melanoma to trail-induced apoptosis and chemotherapy

Melanoma is frequently resistant to a wide range of chemotherapeutic and biologic agents. In its early stages, it is also very immunogenic and gives rise to both T cell and antibody responses. Killing of melanoma by T cells involves induction of apoptosis through the mitochondrial pathway and shares common apoptotic pathways to that induced by chemotherapy. We considered it was therefore possible that prolonged exposure to the immune system may generate escape variants that are resistant to apoptosis induced by the immune system or by chemotherapy. This hypothesis was tested by generating melanoma cells that were resistant to TNF-related apoptosis inducing ligand (TRAIL), which is one of the mediators of apoptosis used by the immune system. Melanoma cells selected in this way were found to be resistant to apoptosis induced by cisplatin, vincristine and a histone deacetylase inhibitor. Melanoma cells resistant to these agents had low levels of pro-apoptotic Bcl-2 (BH3 only) proteins and high levels of activated ERK1/2 and Akt signal pathways. Inhibition of the latter pathways partially overcame some of the resistance to the chemotherapy agents but not to TRAIL. These results support the view that selection by the immune system may in part be responsible for resistance of melanoma to some chemotherapy commonly used against melanoma. Further study of the resistant mechanisms involved may provide insights into new treatment approaches in melanoma.