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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


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 (2020). EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand. Neuro-oncology advances, 2(1):vdz051.

Abstract

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.

Abstract

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2020
Deposited On:14 Dec 2020 18:09
Last Modified:01 Jan 2021 20:51
Publisher:Oxford University Press
ISSN:2632-2498
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Neuro-oncology advances following peer review. The definitive publisher-authenticated version Hoogstrate Y, Vallentgoed W, Kros JM, de Heer I, de Wit M, Eoli M, Sepulveda JM, Walenkamp AME, Frenel JS, Franceschi E, Clement PM, Weller M, van Royen ME, Ansell P, Looman J, Bain E, Morfouace M, Gorlia T, Golfinopoulos V, van den Bent M, French PJ. EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand. Neurooncol Adv. 2019 Dec 9;2(1):vdz051. doi: 10.1093/noajnl/vdz051 is available online at:https://academic.oup.com/noa/article/2/1/vdz051/5669992
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/noajnl/vdz051
PubMed ID:32642719

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