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Berlin Brandenburg

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  • 1
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2016, Vol.1395, pp.E1
    ISSN: 10643745
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 2
    Language: English
    In: Journal of Proteomics, 06 January 2018, Vol.170, pp.130-140
    Description: Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance. Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.
    Keywords: Phosphoproteomics ; Kinase Inhibitors ; Drug Resistance ; Pazopanib ; Dasatinib ; Cell Signalling ; Anatomy & Physiology
    ISSN: 1874-3919
    E-ISSN: 18767737
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  • 3
    Language: English
    In: Oncotarget, 27 September 2016, Vol.7(39), pp.62939-62953
    Description: Tumour cell-extracellular matrix (ECM) interactions are fundamental for discrete steps in breast cancer progression. In particular, cancer cell adhesion to ECM proteins present in the microenvironment is critical for accelerating tumour growth and facilitating metastatic spread. To assess the utility of tumour cell-ECM adhesion as a means for discovering prognostic factors in breast cancer survival, here we perform a systematic phenotypic screen and characterise the adhesion properties of a panel of human HER2 amplified breast cancer cell lines across six ECM proteins commonly deregulated in breast cancer. We determine a gene expression signature that defines a subset of cell lines displaying impaired adhesion to laminin. Cells with impaired laminin adhesion showed an enrichment in genes associated with cell motility and molecular pathways linked to cytokine signalling and inflammation. Evaluation of this gene set in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort of 1,964 patients identifies the F12 and STC2 genes as independent prognostic factors for overall survival in breast cancer. Our study demonstrates the potential of in vitro cell adhesion screens as a novel approach for identifying prognostic factors for disease outcome.
    Keywords: Her2 ; Breast Cancer ; Cell Adhesion ; Extracellular Matrix ; Laminin ; Cell Adhesion ; Gene Expression Regulation, Neoplastic ; Breast Neoplasms -- Diagnosis ; Extracellular Matrix -- Metabolism
    E-ISSN: 1949-2553
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  • 4
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2016, Vol.1395, pp.39-53
    Description: Most commonly used anticancer drugs exert their effects mainly by causing DNA damage. The enhancement in DNA damage response (DDR) is considered a key mechanism that enables cancer cells to survive through eliminating the damaged DNA lesions and thereby developing resistance to DNA-damaging agents. This chapter describes the four experimental approaches for studying DDR and genotoxic drug resistance, including the use of γ-H2AX and comet assays to monitor DNA damage and repair capacity as well as the use of clonogenic and β-galactosidase staining assays to assess long-term cell fate after DNA-damaging treatment. Finally, we also present examples of these methods currently used in our laboratory for studying the role of FOXM1 in DNA damage-induced senescence and epirubicin resistance.
    Keywords: Clonogenic Assay ; Comet Assay ; DNA Damage ; Resistance ; Β-Galactosidase Staining ; Γ-H2ax ; DNA Damage ; Drug Resistance, Neoplasm ; Antineoplastic Agents -- Pharmacology ; Comet Assay -- Methods ; Fluorescent Antibody Technique -- Methods
    ISBN: 9781493933471
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Cell Reports, 05 June 2018, Vol.23(10), pp.3042-3055
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications. Jenks et al. demonstrate that enhanced ciliogenesis can facilitate resistance to a number of kinase inhibitors. Both acquired and resistant cells show increases in cilia numbers and length and increased Hedgehog signaling. Targeting ciliogenesis or ciliary signaling overcomes kinase inhibitor resistance.
    Keywords: Cilia ; Kinase Inhibitor ; Resistance ; Hedgehog Pathway ; Fgfr ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 6
  • 7
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications....
    Keywords: Fgfr ; Hedgehog Pathway ; Cilia ; Kinase Inhibitor ; Resistance
    ISSN: 2211-1247
    Source: DataCite
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  • 8
    Language: English
    In: Cell Reports, 25 October 2016, Vol.17(5), pp.1265-1275
    Description: Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies. Malignant rhabdoid tumors (MRTs) are pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Wong et al. show that MRTs display coactivation of PDGFRα and FGFR1 and that dual blockade of these receptors induces apoptosis. These findings present therapeutic opportunities to exploit tyrosine kinase dependencies in cancers with SWI/SNF deficiencies.
    Keywords: Signal Transduction ; Receptor Tyrosine Kinase ; Rhabdoid Tumor ; Tyrosine Kinase Inhibitor ; Swi/Snf ; Smarcb1 ; Pdgfrα ; Fgfr1 ; Pazopanib ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 9
    Language: English
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
    Description: This research was partly funded by the Institute of Cancer Research and by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), CRUK-CI Core Grant (C14303/A17197), and S.H.D. Fellowship (Wellcome Trust/Royal Society [107609]) (to M.D.R.). B.E.T. was supported by an ICR fellowship.
    Keywords: Fgfr ; Hedgehog Pathway ; Cilia ; Kinase Inhibitor ; Resistance
    Source: DSpace@Cambridge
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  • 10
    In: Jenks, Andrew D and Vyse, Simon and Wong, Jocelyn P and Kostaras, Eleftherios and Keller, Deborah and Burgoyne, Thomas and Shoemark, Amelia and Tsalikis, Athanasios and de la Roche, Maike and Michaelis, Martin and Cinatl, Jindrich and Huang, Paul H and Tanos, Barbara E (2018) Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer. Cell reports, 23 (10). pp. 3042-3055.
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 2211-1247
    Source: University of Kent
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