Patient derived melanoma xenografts

New therapies are required for melanoma. Here we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na+/K+ pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combine with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or hematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation, and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homeostasis in cancer cells can thus synergize with targeted agents to promote tumor regression in vivo. In this study the microarray analysis was based on melanomas obtained from 32 patients and melanocytes from 3 donors. Results provide insight into molecular mechanisms underlying melanoma progression. Total of 84 samples including 2-4 biological replicate for each of the 32 melanomas and three melanocytes isolated from different donors.