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Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden..ORCID iD: 0000-0003-1927-555X
Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA..
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Catalonia, Spain..
KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
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2019 (English)In: 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) Published
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.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2019. Vol. 116, no 20, p. 10009-10018
Keywords [en]
cancer, mutational heterogeneity, structural convergence, intermediate, cryptoepitope
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:kth:diva-252604DOI: 10.1073/pnas.1821442116ISI: 000467804000052PubMedID: 31028138Scopus ID: 2-s2.0-85065738222OAI: oai:DiVA.org:kth-252604DiVA, id: diva2:1321982
Note

QC 20190610

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved

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Lindahl, Erik

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Orellana, LauraGustavsson, JohanParisian, Alison D.Cordeiro, Tiago N.Lindahl, Erik
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