Cerivastatin synergizes with trametinib and enhances its efficacy in the therapy of Uveal Melanoma
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PROVIDER: PRJNA874598 | ENA |
REPOSITORIES: ENA
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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
2022-08-31 | GSE212219 | GEO
Project description:BackgroundMetastatic 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.MethodsWe 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.ResultsSynergistic 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.ConclusionStatins can potentiate the efficacy of MEK inhibitors in the therapy of UM.
| S-EPMC9913575 | biostudies-literature
Project description:Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.
| PRJNA640159 | ENA
Project description:Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma
| PRJNA671868 | ENA
Project description:Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mu-tations. These mutations activate downstream MAPK and PI3K/AKT signaling path-ways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in Ras- and Raf-mutant xenograft models without inducing toxicity. These findings demonstrate that LIFR signaling is a critical driver in Ras/Raf-mutant OCa and that dual inhibition of the MEK and LIFR pathways offers a promising strategy to enhance therapeutic efficacy and overcome resistance in KRAS-mutant OCa.
2025-12-03 | GSE306834 | GEO
Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.
2020-05-26 | PXD013988 | Pride
Project description:EC359 enhances trametinib efficacy in Ras/Raf-driven ovarian cancer by suppressing LIFR signaling
| PRJNA1312479 | ENA
Project description:Efficacy of a selective MEK (trametinib) and BRAFV600E (dabrafenib) inhibitors associated with radioactive iodine (RAI) for the treatment of refractory metastatic differentiated thyroid cancer with RAS or BRAFV600E mutation. To evaluate the objective response rate according to RECIST criteria in thyroid cancer patients with metastatic radioactive iodine (RAI) refractory disease, 6 months after a treatment combining in each arm of the phase II trial (patients with RAS mutation or patients with BRAFV600E mutation): - Arm A: 6 weeks of trametinib followed by RAI treatment (5.5 GBq following rhTSH) in patients with RAS mutation - Arm B: 6 weeks of trametinib plus dabrafenib followed by RAI treatment (5.5 GBq following rhTSH) in patients with BRAFV600E mutation
2023-09-01 | E-MTAB-12837 | biostudies-arrayexpress
Project description:HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma
| PRJNA525852 | ENA
Project description:Efficacy of a selective MEK (trametinib) and BRAFV600E (dabrafenib) inhibitors associated with radioactive iodine (RAI) for the treatment of refractory metastatic differentiated thyroid cancer with RAS (current cohort) or BRAFV600E mutation. To evaluate the objective response rate according to RECIST criteria in thyroid cancer patients with metastatic radioactive iodine (RAI) refractory disease, 6 months after a treatment combining in each arm of the phase II trial (patients with RAS mutation or patients with BRAFV600E mutation): - Arm A: 6 weeks of trametinib followed by RAI treatment (5.5 GBq following rhTSH) in patients with RAS mutation - Arm B: 6 weeks of trametinib plus dabrafenib followed by RAI treatment (5.5 GBq following rhTSH) in patients with BRAFV600E mutation
2023-09-01 | E-MTAB-12900 | biostudies-arrayexpress