Structural insights into the role and targeting of EGFRvIII

Atrish Bagchi; Steven E. Stayrook; Katerina T. Xenaki; Chrystal A. Starbird; Sofia Doulkeridou; Rachid el Khoulati; Rob C. Roovers; Karl R. Schmitz; Paul M.P. van Bergen en Henegouwen; Kathryn M. Ferguson

doi:10.1016/j.str.2024.05.018

Structural insights into the role and targeting of EGFRvIII

Atrish Bagchi, Steven E. Stayrook, Katerina T. Xenaki, Chrystal A. Starbird, Sofia Doulkeridou, Rachid el Khoulati, Rob C. Roovers, Karl R. Schmitz, Paul M.P. van Bergen en Henegouwen, Kathryn M. Ferguson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.

Original language	English
Pages (from-to)	1367-1380.e6
Journal	Structure
Volume	32
Issue number	9
Early online date	21 Jun 2024
DOIs	https://doi.org/10.1016/j.str.2024.05.018
Publication status	Published - 5 Sept 2024

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

Funding

We thank Mark Lemmon and members of the Lemmon and Ferguson laboratories for valuable discussion and comments on the manuscript. We thank Judith Kikhney for generation and initial characterization ofs EGFRvIII, Yendi Linares for generation and initial characterization of sEGFRvIIIC283S, Mohammed el Khatabbi for immunization and library construction, and Maaike de Vries and Lisanne Vermeer for contributions to selections and characterization of EGFRvIII VHH domains. This work was supported by NCI grants R01 CA112552 and R01 CA198164 to K.M.F. and by Technology Foundation STW (10074) to R.C.R. A.B. was supported in part by T32-GM008275, and R.e.K. by the Netherlands STOP Brain Tumors Foundation (Stichting STOPhersentumoren) . GM/CA @ APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006) . This research used the resources of the Advanced Photon Sciences, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Funders	Funder number
NCI	R01 CA112552, R01 CA198164
Technology Foundation STW	10074, T32-GM008275
Netherlands STOP Brain Tumors Foundation
National Cancer Institute	ACB-12002
National Institute of General Medical Sciences	AGM-12006
Advanced Photon Sciences, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory	DE-AC02-06CH11357

Keywords

epidermal growth factor receptor
epidermal growth factor receptor variant III
glioblastoma multiforme
nanobody
oncogenic mutation
VHH domain
X-ray crystallography

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.str.2024.05.018

PIIS0969212624001953Final published version, 4.67 MBLicence: Taverne

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title = "Structural insights into the role and targeting of EGFRvIII",

abstract = "The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.",

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author = "Atrish Bagchi and Stayrook, {Steven E.} and Xenaki, {Katerina T.} and Starbird, {Chrystal A.} and Sofia Doulkeridou and {el Khoulati}, Rachid and Roovers, {Rob C.} and Schmitz, {Karl R.} and {van Bergen en Henegouwen}, {Paul M.P.} and Ferguson, {Kathryn M.}",

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year = "2024",

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doi = "10.1016/j.str.2024.05.018",

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AU - Doulkeridou, Sofia

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AU - Roovers, Rob C.

AU - Schmitz, Karl R.

AU - van Bergen en Henegouwen, Paul M.P.

AU - Ferguson, Kathryn M.

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AB - The epidermal growth factor receptor (EGFR) is a well-known oncogenic driver in lung and other cancers. In glioblastoma multiforme (GBM), the EGFR deletion variant III (EGFRvIII) is frequently found alongside EGFR amplification. Agents targeting the EGFR axis have shown limited clinical benefits in GBM and the role of EGFRvIII in GBM is poorly understood. To shed light on the role of EGFRvIII and its potential as a therapeutic target, we determined X-ray crystal structures of a monomeric EGFRvIII extracellular region (ECR). The EGFRvIII ECR resembles the unliganded conformation of EGFR, including the orientation of the C-terminal region of domain II. Domain II is mostly disordered, but the ECR structure is compact. We selected a nanobody with preferential binding to EGFRvIII relative to EGFR and structurally defined an epitope on domain IV that is occluded in the unliganded intact EGFR. These findings suggest new avenues for EGFRvIII targeting in GBM.

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Structural insights into the role and targeting of EGFRvIII

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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