Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

Liu, Jeff C.; Granieri, Letizia; Shrestha, Mariusz; Wang, Dong‐Yu; Vorobieva, Ioulia; Rubie, Elizabeth A.; Jones, Robert A.; Ju, Youngjun; Pellecchia, Giovanna; Jiang, Zhe; Palmerini, Carlo Alberto; Ben‐David, Yaacov; Egan, Sean E.; Woodgett, James R.; Bader, Gary D.; Datti, Alessandro; Zacksenhaus, Eldad

doi:10.1016/j.celrep.2018.03.039

Cited by 65 publications

(52 citation statements)

References 58 publications

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“…Furthermore, it has been suggested that the FGF3 mediated RAS activation (Control #14) can lead to Vemurafenib resistance in melanoma cells [51]. Interestingly, inhibiting the CDC25 (Control # 9) family has been suggested as a potential therapeutic for triple negative breast cancer [28], and we see that knocking down CDC25A results in no proliferative steady states.…”

Section: Avoiding Proliferative Steady Statesmentioning

confidence: 58%

Control of Intracellular Molecular Networks Using Algebraic Methods

Vieira

Laubenbacher²,

Murrugarra

2019

Preprint

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Many problems in biology and medicine have a control component. Often, the goal might be to modify intracellular networks, such as gene regulatory networks or signaling networks, in order for cells to achieve a certain phenotype, such as happens in cancer. If the network is represented by a mathematical model for which mathematical control approaches are available, such as systems of ordinary differential equations, then this problem might be solved systematically. Such approaches are available for some other model types, such as Boolean networks, where structurebased approaches have been developed, as well as stable motif techniques.

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Section: Avoiding Proliferative Steady Statesmentioning

confidence: 58%

Control of Intracellular Molecular Networks Using Algebraic Methods

Vieira

Laubenbacher²,

Murrugarra

2019

Preprint

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“…Constant monitoring is essentially intended to assess resistance (Komarova & Wodarz, 2005) and reveal pathways to which tumors may become addicted during treatment (Luo, Solimini et al, 2009). CDC25 phosphatases are overexpressed in a variety of human cancers (Boutros et al, 2007, Kristjansdottir & Rudolph, 2004, are rate-limiting in tumorigenesis induced by Ras (Ray & Kiyokawa, 2008), and were recently proposed as target of choice in unresponsive, triple-negative breast cancer (Liu et al, 2018). In this study we set out to identify novel CDC25 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…In light of the recent discovery that CDC25 is the therapeutic target of choice in triple-negative breast cancers, namely those that are negative for estrogen-, progesterone-and HER2-receptor expression and that are unresponsive to standard therapy (Liu, Granieri et al, 2018), we set out to develop novel CDC25 inhibitors. To this end, we conducted a pharmacophore-guided drug discovery program that led to the identification of novel scaffolds of the naphthoquinone group displaying inhibition of CDC25 in enzymatic assays.…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and cell death

Kabakci

Käppeli

Cozza

et al. 2018

Preprint

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CDC25 phosphatases have a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors.Using a combination of computational approaches we defined a minimal common pharmacophore in established CDC25 inhibitors and performed a virtual screening of a proprietary library. Taking advantage of the availability of crystal structures for CDC25A and CDC25B and using a molecular docking strategy, we carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, studies on 3D organoids derived from intestinal crypt stem cells of Apc/K-Ras mice revealed that the compounds caused arrest of proliferation.All rights reserved. No reuse allowed without permission.

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“…2d). Noteworthy, this analysis returned the CDC25B gene, known to be involved in breast cancer and being a potential therapeutic target 33 .…”

Section: H3k27ac Marks Across Tissues and Diseases H3k27ac Epigenetimentioning

confidence: 99%

Ontology-driven integrative analysis of omics data through Onassis

Galeota

Kishore

Pelizzola

2020

Sci Rep

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public repositories of large-scale omics datasets represent a valuable resource for researchers. in fact, data re-analysis can either answer novel questions or provide critical data able to complement in-house experiments. However, despite the development of standards for the compilation of metadata, the identification and organization of samples still constitutes a major bottleneck hampering data reuse. We introduce Onassis, an R package within the Bioconductor environment providing key functionalities of natural Language processing (nLp) tools. Leveraging biomedical ontologies, onassis greatly simplifies the association of samples from large-scale repositories to their representation in terms of ontology-based annotations. Moreover, through the use of semantic similarity measures, onassis hierarchically organizes the datasets of interest, thus supporting the semantically aware analysis of the corresponding omics data. in conclusion, onassis leverages nLp techniques, biomedical ontologies, and the R statistical framework, to identify, relate, and analyze datasets from public repositories. The tool was tested on various large-scale datasets, including compendia of gene expression, histone marks, and DnA methylation, illustrating how it can facilitate the integrative analysis of various omics data.

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Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

Cited by 65 publications

References 58 publications

Control of Intracellular Molecular Networks Using Algebraic Methods

Control of Intracellular Molecular Networks Using Algebraic Methods

Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and cell death

Ontology-driven integrative analysis of omics data through Onassis

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