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EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand

BACKGROUND: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed tr...

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Autores principales: Hoogstrate, Youri, Vallentgoed, Wies, Kros, Johan M, de Heer, Iris, de Wit, Maurice, Eoli, Marica, Sepulveda, Juan Manuel, Walenkamp, Annemiek M E, Frenel, Jean-Sebastien, Franceschi, Enrico, Clement, Paul M, Weller, Micheal, van Royen, Martin E, Ansell, Peter, Looman, Jim, Bain, Earle, Morfouace, Marie, Gorlia, Thierry, Golfinopoulos, Vassilis, van den Bent, Martin, French, Pim J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878/
https://www.ncbi.nlm.nih.gov/pubmed/32642719
http://dx.doi.org/10.1093/noajnl/vdz051
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author Hoogstrate, Youri
Vallentgoed, Wies
Kros, Johan M
de Heer, Iris
de Wit, Maurice
Eoli, Marica
Sepulveda, Juan Manuel
Walenkamp, Annemiek M E
Frenel, Jean-Sebastien
Franceschi, Enrico
Clement, Paul M
Weller, Micheal
van Royen, Martin E
Ansell, Peter
Looman, Jim
Bain, Earle
Morfouace, Marie
Gorlia, Thierry
Golfinopoulos, Vassilis
van den Bent, Martin
French, Pim J
author_facet Hoogstrate, Youri
Vallentgoed, Wies
Kros, Johan M
de Heer, Iris
de Wit, Maurice
Eoli, Marica
Sepulveda, Juan Manuel
Walenkamp, Annemiek M E
Frenel, Jean-Sebastien
Franceschi, Enrico
Clement, Paul M
Weller, Micheal
van Royen, Martin E
Ansell, Peter
Looman, Jim
Bain, Earle
Morfouace, Marie
Gorlia, Thierry
Golfinopoulos, Vassilis
van den Bent, Martin
French, Pim J
author_sort Hoogstrate, Youri
collection PubMed
description BACKGROUND: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment. METHODS: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit. RESULTS: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody–drug conjugate. We also identified tumors harboring mutations sensitive to “classical” EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy. CONCLUSIONS: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.
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spelling pubmed-72128782020-07-07 EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand Hoogstrate, Youri Vallentgoed, Wies Kros, Johan M de Heer, Iris de Wit, Maurice Eoli, Marica Sepulveda, Juan Manuel Walenkamp, Annemiek M E Frenel, Jean-Sebastien Franceschi, Enrico Clement, Paul M Weller, Micheal van Royen, Martin E Ansell, Peter Looman, Jim Bain, Earle Morfouace, Marie Gorlia, Thierry Golfinopoulos, Vassilis van den Bent, Martin French, Pim J Neurooncol Adv Basic and Translational Investigations BACKGROUND: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment. METHODS: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit. RESULTS: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody–drug conjugate. We also identified tumors harboring mutations sensitive to “classical” EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy. CONCLUSIONS: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors. Oxford University Press 2019-12-09 /pmc/articles/PMC7212878/ /pubmed/32642719 http://dx.doi.org/10.1093/noajnl/vdz051 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic and Translational Investigations
Hoogstrate, Youri
Vallentgoed, Wies
Kros, Johan M
de Heer, Iris
de Wit, Maurice
Eoli, Marica
Sepulveda, Juan Manuel
Walenkamp, Annemiek M E
Frenel, Jean-Sebastien
Franceschi, Enrico
Clement, Paul M
Weller, Micheal
van Royen, Martin E
Ansell, Peter
Looman, Jim
Bain, Earle
Morfouace, Marie
Gorlia, Thierry
Golfinopoulos, Vassilis
van den Bent, Martin
French, Pim J
EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title_full EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title_fullStr EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title_full_unstemmed EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title_short EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
title_sort egfr mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878/
https://www.ncbi.nlm.nih.gov/pubmed/32642719
http://dx.doi.org/10.1093/noajnl/vdz051
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