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  • 1. Binder, Zev A.
    et al.
    Haseley Thorne, Amy
    Bakas, Spyridon
    Wileyto, E. Paul
    Bilello, Michel
    Akbari, Hamed
    Rathore, Saima
    Ha, Sung Min
    Zhang, Logan
    Ferguson, Cole J.
    Dahiya, Sonika
    Bi, Wenya Linda
    Reardon, David A.
    Idbaih, Ahmed
    Felsberg, Joerg
    Hentschel, Bettina
    Weller, Michael
    Bagley, Stephen J.
    Morrissette, Jennifer J. D.
    Nasrallah, MacLean P.
    Ma, Jianhui
    Zanca, Ciro
    Scott, Andrew M.
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Davatzikos, Christos
    Furnari, Frank B.
    O'Rourke, Donald M.
    Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development2018In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 34, no 1, p. 163-177Article in journal (Refereed)
    Abstract [en]

    We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR(A289D/T/V)). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR(A289D/T/V) mutants, corroborated in mice bearing intracranial tumors expressing EGFR(A289V) and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR(A289V) tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR(A289V) mutation in glioblastoma, postulating EGFR(A289V) as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.

  • 2. Ma, Jianhui
    et al.
    Benite, Jorge A.
    Li, Jie
    Miki, Shunichiro
    de Albuquerqu, Claudio Ponte
    Galatro, Thais
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Zanca, Ciro
    Reed, Rachel
    Boyer, Antonia
    Koga, Tomoyuki
    Varki, Nissi M.
    Fenton, Tim R.
    Marie, Suely Kazue Nagahashi
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Gahman, Timothy C.
    Shiau, Andrew K.
    Zhou, Huilin
    DeGroot, John
    Sulman, Erik P.
    Cavenee, Webster K.
    Kolodner, Richard D.
    Chen, Clark C.
    Furnari, Frank B.
    Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair2019In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed)
    Abstract [en]

    Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

  • 3.
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Convergence of EGFR glioblastoma mutations: evolution and allostery rationalizing targeted therapy2019In: Molecular & Cellular Oncology, E-ISSN 2372-3556, Vol. 6, no 5, article id e1630798Article in journal (Refereed)
    Abstract [en]

    EGFR mutations display striking organ-site asymmetry and heterogeneity. We have shown that structurally diverse extracellular mutations, typical of glioblastomas, converge to a similar intermediate conformation, which can be synergistically targeted extra- and intracelullarly by antibody mAb806 and type-II kinase inhibitors. Our findings reveal convergence behind heterogeneity, paving the way for allostery-based co-targeting.

  • 4.
    Orellana, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Gustavsson, Johan
    Bergh, Cathrine
    Yoluk, Ozge
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces2019In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 18, p. 3505-3507Article in journal (Refereed)
    Abstract [en]

    Understanding how proteins transition between different conformers, and how conformers relate to each other in terms of structure and function, is not trivial. Here, we present an online tool for transition pathway generation between two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts transition intermediates trapped experimentally. In addition to path-generation, the server provides an interactive 2D-motion landscape graphical representation of the transitions or any additional conformers to explore their structural relationships.

  • 5.
    Orellana, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Thorne, Amy H.
    Lema, Rafael
    Gustavsson, Johan
    Parisian, Alison D.
    Hospital, Adam
    Cordeiro, Tiago N.
    Bernado, Pau
    Scott, Andrew M.
    Brun-Heath, Isabelle
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cavenee, Webster K.
    Furnari, Frank B.
    Orozco, Modesto
    Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 20, p. 10009-10018Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.

  • 6.
    Qureshi, Abdul Aziz
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Suades, Albert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Matsuoka, Rei
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brock, Joseph
    McComas, Sarah
    Nji, Emmanuel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Orellana, Laura
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Claesson, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Delemotte, Lucie
    Drew, David
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Malarial parasite transporter structure reveals the molecular basis for sugar importManuscript (preprint) (Other academic)
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