Dataset Information

Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma.

ABSTRACT:

Background

Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-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.

SUBMITTER: Amaro AA

PROVIDER: S-EPMC9913575 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma.

Amaro Adriana Agnese AA Gangemi Rosaria R Emionite Laura L Castagnola Patrizio P Filaci Gilberto G Jager Martine J MJ Tanda Enrica Teresa ET Spagnolo Francesco F Mascherini Matteo M Pfeffer Ulrich U Croce Michela M

Cancers 20230131 3

<h4>Background</h4>Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-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 tha ...[more]

PMID: 36765842

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Project description:Background and Aims: Uveal melanoma (UM), the most common primary intraocular tumor in adults, is characterized by marked variability in its ability to metastasize. In fact, up to half the patients with UM develop distant metastases, most commonly to the liver. Mutations in alpha G-protein subunits, GNAQ and GNA11, are found in most primary UM, in a mutually exclusive pattern. Also, mutations in SF3B1, EIF1AX, and BAP1, are associated with markedly distinct prognoses Targeted therapy with MAP kinase inhibitors has been unsuccessful in the treatment of uveal melanoma (UM). The constitutive activation of GNAq and GNA11, typical of MU, determines the activation not only of the MAP kinases but also of the transcription factors YAP / TAZ. It is known that when statins are used to inhibit the HMGCR activity in the mevalonate pathway, the nuclear localization and transcriptional activity of YAP-TAZ are also inhibited mediating a potential anti-cancer activity Methods: We investigated the sensitivity to drugs of a panel of 6 lines of MU, two metastatic and 4 derived from primary tumors, of the latter two were monosomic. We established the IC50s of the individual drugs and the effects of the combinations. The synergistic effects of drugs were studied using MTT proliferation tests, cell cycle and apoptosis. The most synergistic combination was tested in vivo in NSG mice. Results: The synergistic concentrations of trametinib and cerivastatin (T+C) induced a massive arrest of proliferation and cell cycle and an increase of apoptosis 72 hours after the start of treatment particularly in the monosomic, BAP1 mutated UPMM3 cell line. The synergistic effect of T+C was reached after 7 instead of 3 days. In the metastatic OMM2.5 cell line. T+C treatments reduced ERK and AKT phosphorylation and increased the cytoplasmatic, inactive form of YAP. T+C treatment of NSG mice transplanted with the monosomic UM cell line reduced significantly tumor growth. Conclusion: This study suggests that statins potentiate the efficacy of MEK inhibitors in the therapy of UM

Dataset Information

Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma.

Background

Methods

Results

Conclusion

Publications

Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma.

Similar Datasets

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