panobinostat and Uveal-Neoplasms

The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.. 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 advanced uveal melanoma.

Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Humans; MAP Kinase Signaling System; Melanoma; Mice; Panobinostat; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Receptor Tyrosine Kinase-like Orphan Receptors; Receptor, IGF Type 1; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factors; Uveal Neoplasms; Xenograft Model Antitumor Assays

Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma (UM) and metastasis. The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM.. In silico screens were done to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, bromodeoxyuridine incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model.. Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo.. These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chemoradiotherapy, Adjuvant; Computer Simulation; Gene Knockdown Techniques; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Melanoma; Mice; Mice, Inbred NOD; Mice, SCID; Models, Biological; Neoplasm Micrometastasis; Panobinostat; Tumor Burden; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Uveal Neoplasms; Valproic Acid; Vorinostat; Xenograft Model Antitumor Assays