Cerivastatin synergizes with trametinib and enhances its efficacy in the therapy of uveal melanoma

Amaro, A.A.; Gangemi, R.; Emionite, L.; Castagnola, P.; Filaci, G.; Jager, M.J.; Tanda, E.T.; Spagnolo, F.; Mascherini, M.; Pfeffer, U.; Croce, M.

doi:doi:10.3390/cancers15030886

Simple Summary Uveal melanoma is a rare and aggressive disease. G alpha-proteins GNAQ and GNA11 are driver mutations that activate MAP kinase and YAP/TAZ pathways. BAP1 loss and monosomy of chromosome 3 are present in patients with high risk of metastasis. MEK-inhibitors do not significantly block UM progression. Combinations of the MEK inhibitor trametinib and different classes of drugs targeting YAP/TAZ were used to overcome resistance. Combination of trametinib and cerivastatin were synergistic in vitro and in vivo in BAP1 mutated and chromosome 3 monosomic uveal melanoma cell lines. Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in G alpha-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway,...Show moreSimple Summary Uveal melanoma is a rare and aggressive disease. G alpha-proteins GNAQ and GNA11 are driver mutations that activate MAP kinase and YAP/TAZ pathways. BAP1 loss and monosomy of chromosome 3 are present in patients with high risk of metastasis. MEK-inhibitors do not significantly block UM progression. Combinations of the MEK inhibitor trametinib and different classes of drugs targeting YAP/TAZ were used to overcome resistance. Combination of trametinib and cerivastatin were synergistic in vitro and in vivo in BAP1 mutated and chromosome 3 monosomic uveal melanoma cell lines. Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in G alpha-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway, geranyl-geranylation, and subcellular localisation of the Rho-GTPase. We investigated drugs that affect the YAP/TAZ pathway, valproic acid, verteporfin and statins, in combination with MEK-inhibitor trametinib. Methods: We established IC50 values of the individual drugs and monitored the effects of their combinations in terms of proliferation. We selected trametinib and cerivastatin for evaluation of cell cycle and apoptosis. Synergism was detected using isobologram and Chou-Talalay analyses. The most synergistic combination was tested in vivo. Results: Synergistic concentrations of trametinib and cerivastatin induced a massive arrest of proliferation and cell cycle and enhanced apoptosis, particularly in the monosomic, BAP1-mutated UPMM3 cell line. The combined treatment reduced ERK and AKT phosphorylation, increased the inactive, cytoplasmatic form of YAP and significantly impaired the growth of UM cells with monosomy of chromosome 3 in NSG mice. Conclusion: Statins can potentiate the efficacy of MEK inhibitors in the therapy of UM.Show less

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Cerivastatin synergizes with trametinib and enhances its efficacy in the therapy of uveal melanoma