Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation

SIMPLE SUMMARY: Spitzoid melanoma is a rare tumor type and so far preclinical models for translational research have also been also lacking. We established a cell line from a metastatic spitzoid melanoma that is, according to our knowledge, the first cell model from this tumor type. The cells carried a novel activating mutation in the region of the MEK1 protein that influences the sensitivity of the mutant protein to MEK inhibitors. We tested the cells’ sensitivity to clinically used and newly developed MEK inhibitors in both in vitro and in vivo models. The clinically approved MEK inhibitor strongly reduced both in vitro and in vivo tumor growth and might be an effective therapy for tumors with this kind of MEK mutation. ABSTRACT: Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib—but not selumentinib—and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.