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1.
  • Gad, Helge, et al. (author)
  • MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
  • 2014
  • In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
  • Journal article (peer-reviewed)abstract
    • Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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2.
  • Schmidt, L., et al. (author)
  • Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions
  • 2013
  • In: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 15:11, s. 1469-1478
  • Journal article (peer-reviewed)abstract
    • Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Of the 5 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.
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  • Result 1-2 of 2
Type of publication
journal article (2)
Type of content
peer-reviewed (2)
Author/Editor
Martens, Ulf (2)
Häggblad, Maria (2)
Lundgren, Bo (2)
Johansson, Lars (1)
Henriksson, Martin (1)
Johansson, Fredrik (1)
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Helleday, Thomas (1)
Olsson, M. (1)
Westermark, Bengt (1)
Loseva, Olga (1)
Artursson, Per (1)
Hammarström, Lars G. ... (1)
Svensson, Richard (1)
Jenmalm Jensen, Anni ... (1)
Lundbäck, Thomas (1)
Lundin, Cecilia (1)
Schultz, Niklas (1)
Nelander, Sven (1)
Gustafsson, Robert (1)
Axelsson, Hanna (1)
Altun, Mikael (1)
Jeppsson, Fredrik (1)
Djureinovic, Tatjana (1)
Gerlee, Philip, 1980 (1)
Stenmark, Pål (1)
Nilsson, Jonas A, 19 ... (1)
Hansson, C (1)
Schmidt, L (1)
Wallner, Olov A. (1)
Uhrbom, Lene (1)
Nilsson, Karin Forsb ... (1)
Gad, Helge (1)
Baskaran, Sathishkum ... (1)
Saleh, Aljona (1)
Einarsdottir, Bergli ... (1)
Gaugaz, Fabienne Z. (1)
Baranczewski, Pawel (1)
Berntsson, Ronnie P. ... (1)
Svensson, Linda M. (1)
Pham, Therese (1)
Scobie, Martin (1)
Höglund, Andreas (1)
Göktürk, Camilla (1)
Wiita, Elisee (1)
Vallin, Karl S. A. (1)
Jemth, Ann-Sofie (1)
Sanjiv, Kumar (1)
Desroses, Matthieu (1)
Kalderen, Christina (1)
Koolmeister, Tobias (1)
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University
University of Gothenburg (2)
Uppsala University (2)
Stockholm University (2)
Linköping University (1)
Chalmers University of Technology (1)
Karolinska Institutet (1)
Language
English (2)
Research subject (UKÄ/SCB)
Natural sciences (2)
Medical and Health Sciences (2)

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