Identification of Aneuploidy-Selective Antiproliferation Compounds

David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
Cell (Impact Factor: 32.24). 02/2011; 144(4):499-512. DOI: 10.1016/j.cell.2011.01.017
Source: PubMed


Aneuploidy, an incorrect chromosome number, is a hallmark of cancer. Compounds that cause lethality in aneuploid, but not euploid, cells could therefore provide new cancer therapies. We have identified the energy stress-inducing agent AICAR, the protein folding inhibitor 17-AAG, and the autophagy inhibitor chloroquine as exhibiting this property. AICAR induces p53-mediated apoptosis in primary mouse embryonic fibroblasts (MEFs) trisomic for chromosome 1, 13, 16, or 19. AICAR and 17-AAG, especially when combined, also show efficacy against aneuploid human cancer cell lines. Our results suggest that compounds that interfere with pathways that are essential for the survival of aneuploid cells could serve as a new treatment strategy against a broad spectrum of human tumors.

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Available from: Bret R Williams, Oct 22, 2014
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    • "Clinically, chromosomal instability is associated with poor prognosis and therapeutic resistance (Bakhoum et al., 2011; Lee et al., 2011; Ryan et al., 2012); however, excessive instability results in a superior treatment response (Bakhoum et al., 2015; Birkbak et al., 2011; Roylance et al., 2011; Zaki et al., 2014). Our work provides experimentally testable predictions and sheds quantitative insight into ongoing efforts that aim to specifically target chromosomally unstable and aneuploid cancer cells (Janssen et al., 2009; Tang et al., 2011). "
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    ABSTRACT: Numerical chromosomal instability is a ubiquitous feature of human neoplasms. Due to experimental limitations, fundamental characteristics of karyotypic changes in cancer are poorly understood. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we show that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimizes phenotypic heterogeneity and clonal survival. Departure from this range reduces clonal fitness and limits subclonal diversity. Mapping of the aneuploid fitness landscape reveals a highly favorable, commonly observed, near-triploid state onto which evolving diploid- and tetraploid-derived populations spontaneously converge, albeit at a much lower fitness cost for the latter. Finally, by analyzing 1,368 chromosomal translocation events in five human cancers, we find that karyotypic evolution also shapes chromosomal translocation patterns by selecting for more oncogenic derivative chromosomes. Thus, chromosomal instability can generate the heterogeneity required for Darwinian tumor evolution. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell Reports
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    • "YSCBI-1192; No. of Pages 7 N. Dejeans et al. / Seminars in Cancer Biology xxx (2015) xxx–xxx 3 aneuploidy was found to be associated to hypersensitivity to conditions interfering with protein synthesis and protein folding in yeast [24] and in human cancer cells [25], and that MYC transformation requires a reliable secretory pathway to mediate its oncogenic potential [26]. Moreover, cell transformation can result in an increase in proliferation and metabolic demand, thereby leading to nutrient (i.e. "
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    ABSTRACT: The hallmarks of cancer currently define the molecular mechanisms responsible for conferring specific tumor phenotypes. Recently, these characteristics were also connected to the status of the secretory pathway, thereby linking the functionality of this cellular machinery to the acquisition of cancer cell features. The secretory pathway ensures the biogenesis of proteins that are membrane-bound or secreted into the extracellular milieu and can control its own homeostasis through an adaptive signaling pathway named the Unfolded Protein Response (UPR). In the present review, we discuss the specific features of the UPR in various tumor types and the impact of the selective activation of this pathway on cell transformation, tumor development and aggressiveness. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · May 2015 · Seminars in Cancer Biology
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    • "The aneuploidy-specific lethal effect of AICAR is synergistic with 17-allyamino-17-demethoxy- geldanamycin (17-AAG), an inhibitor of the chaperone Hsp90. Importantly, the combined use of AICAR and 17-AAG showed increased lethality for human aneuploid cell lines with CIN compared with non-CIN cells (Tang et al. 2011). Both of these molecules are in clinical trials, although 17-AAG has not proven to be effective in cancer patients and is associated with toxic side effects (Heath et al. 2008; Solit et al. 2008; Gartner et al. 2012; Saif et al. 2013). "
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    ABSTRACT: Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of cancer. Paradoxically, aneuploidy generally has a negative impact on cell growth and fitness in nontransformed cells. In this work, we review recent progress in identifying how aneuploidy leads to genomic and chromosomal instability, how cells can adapt to the deleterious effects of aneuploidy, and how aneuploidy contributes to tumorigenesis in different genetic contexts. Finally, we also discuss how aneuploidy might be a target for anticancer therapies.
    Preview · Article · Sep 2014 · Cold Spring Harbor perspectives in biology
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