211 research outputs found
Abstract 4154: Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma
No full textAbstract
Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. Currently available drugs have shown limited clinical activity in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells are sensitive to BET inhibitors (BETi) through the induction of cell cycle arrest and apoptosis. However, despite the initial inhibitory effects, UM cells acquire resistance to this class of drugs following chronic drug exposure. In order to understand the mechanistic basis for BETi resistance in UM, we assessed genome-wide CpG methylation patterns in UM cell lines that had been rendered resistant to the clinical BET inhibitor PLX51107 (Plexxikon, Berkeley, CA) following chronic drug exposure. The comparison between BET inhibitor-resistant versus sensitive cell lines revealed differential methylation of 1700 genes, including several involved in Wnt/β-catenin signaling, as well as other signaling pathways. Immunoblotting analysis confirmed that β-catenin protein was induced and activated in the resistant cells, while depletion of β-catenin by siRNA re-sensitized the resistant cells to the BET inhibitor. We then explored several combinations of PLX51107 with drugs that block β-catenin transcriptional activity through inhibition of its phosphorylation by PAK4 or through the inhibition of binding partners like Cdk8 and CBP. All these combinations increased the activity of the BET inhibitor in both sensitive and resistant cells, and these effects were synergistic, with combination indexes (CI) <1. These observations support the evidence that acquired resistant to BET inhibitors is mediated, at least in part, by activation of the Wnt/β-catenin pathway, and inhibitors of this pathway may provide a means to overcome acquired BET inhibitor resistance in UM patients treated with this class of drugs.
Citation Format: Grazia Ambrosini, Benjamin Tycko, Chaterine Do, Gary K. Schwartz. Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4154. doi:10.1158/1538-7445.AM2017-4154</jats:p
Mapping Allele-Specific DNA Methylation: A New Tool for Maximizing Information from GWAS
No full textIn this issue of The Journal, an article by Schalkwyk et al.1 shows the landscape of allele-specific DNA methylation (ASM) in the human genome. ASM has long been studied as a hallmark of imprinted genes, and a chromosome-wide version of this phenomenon occurs, in a random fashion, during X chromosome inactivation in female cells. But the type of ASM motivating the study by Schalkwyk et al. is different. They used a high-resolution, methylation-sensitive SNP array (MSNP) method for genome-wide profiling of ASM in total peripheral-blood leukocytes (PBL) and buccal cells from a series of monozygotic twin pairs. Their data bring a new level of detail to our knowledge of a newly recognized phenomenon—nonimprinted, sequence-dependent ASM. They document the widespread occurrence of this phenomenon among human genes and discuss its basic implications for gene regulation and genetic-epigenetic interactions. But this paper and recent work from other laboratories2,3 raises the possibility of a more immediate and practical application for ASM mapping, namely to help extract maximum information from genome-wide association studies
Consenting to Early Modern Empires: Introduction
No full textThis text offers an introduction to the special theme section on Consenting to Early Modern Empires, guest-edited by the author. The contributors to this section seek to explain the prominent place given to consent in Spanish-American and Portuguese-Asian imperial records. This introduction points out that the politics of consent in early modern empires did not reside primarily in a struggle between freedom and unfreedom. Indigenous strategies of using consent to place checks on the Spanish and Portuguese had the effect of integrating them further into European empires
Abstract ED02-02: Interaction between genetics, epigenetics, and environment in cancer prevention
No full text
Recommended from our members
Publisher Correction: Pairwise library screen systematically interrogates Staphylococcus aureus Cas9 specificity in human cells
No full textThe original HTML version of this Article incorrectly listed an affiliation of Josh Tycko as 'Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA', instead of the correct 'Present address: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA'. It also incorrectly listed an affiliation of this author as 'Present address: Arrakis Therapeutics, 35 Gatehouse Dr., Waltham, MA, 02451, USA'.The original HTML version incorrectly listed an affiliation of Luis A. Barrera as 'Present address: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06511, USA', instead of the correct 'Present address: Arrakis Therapeutics, 35 Gatehouse Dr., Waltham, MA 02451, USA'.Finally, the original HTML version incorrectly omitted an affiliation of Nicholas C. Huston: 'Present address: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA'.This has been corrected in the HTML version of the Article. The PDF version was correct from the time of publication
- …
