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Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies


Roth, P; Weller, M (2014). Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro-Oncology, 16(suppl 8):viii14-viii19.

Abstract

Epidermal growth factor receptor (EGFR) gene amplification and activating mutations are common findings in glioblastomas. EGFR is at the top of a downstream signaling cascade that regulates important characteristics of glioblastoma cells, including cellular proliferation, migration, and survival. Targeting EGFR has therefore been regarded as a promising therapeutic strategy in glioblastoma for decades. However, although various pharmacological inhibitors and anti-EGFR antibodies are available, the antiglioma activity of these agents has been largely limited to preclinical models, whereas their administration to glioblastoma patients was characterized by lack of clinical benefit. Comprehensive efforts have been made within the last years to understand the underlying mechanisms that confer resistance to EGFR inhibition in glioma cells. The absence of well-known mutations that predict response to EGFR tyrosine kinase inhibitors (TKIs) in gliomas as well as the presence of redundant and alternative compensatory pathways are among the most important escape mechanisms that prevent potent antiglioma effects of EGFR-targeting drugs. Accordingly, an increasing number of in vitro and in vivo studies are aimed at overcoming this resistance by combinatorial approaches using anti-EGFR treatment together with one or more additional drugs. Novel insights into the molecular mechanisms mediating resistance to anti-EGFR treatment and promising combinatorial approaches may help to better define a future role for EGFR inhibition in the treatment of glioblastoma.

Abstract

Epidermal growth factor receptor (EGFR) gene amplification and activating mutations are common findings in glioblastomas. EGFR is at the top of a downstream signaling cascade that regulates important characteristics of glioblastoma cells, including cellular proliferation, migration, and survival. Targeting EGFR has therefore been regarded as a promising therapeutic strategy in glioblastoma for decades. However, although various pharmacological inhibitors and anti-EGFR antibodies are available, the antiglioma activity of these agents has been largely limited to preclinical models, whereas their administration to glioblastoma patients was characterized by lack of clinical benefit. Comprehensive efforts have been made within the last years to understand the underlying mechanisms that confer resistance to EGFR inhibition in glioma cells. The absence of well-known mutations that predict response to EGFR tyrosine kinase inhibitors (TKIs) in gliomas as well as the presence of redundant and alternative compensatory pathways are among the most important escape mechanisms that prevent potent antiglioma effects of EGFR-targeting drugs. Accordingly, an increasing number of in vitro and in vivo studies are aimed at overcoming this resistance by combinatorial approaches using anti-EGFR treatment together with one or more additional drugs. Novel insights into the molecular mechanisms mediating resistance to anti-EGFR treatment and promising combinatorial approaches may help to better define a future role for EGFR inhibition in the treatment of glioblastoma.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Date:October 2014
Deposited On:05 Nov 2014 17:18
Last Modified:08 Dec 2017 07:56
Publisher:Oxford University Press
ISSN:1522-8517
Additional Information:This is a pre-copyedited, author-produced PDF of an article accepted for publication in Neuro-Oncology following peer review. The definitive publisher-authenticated version Roth, P; Weller, M (2014). Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro-Oncology, 16(suppl 8):viii14-viii19. is available online at: http://neuro-oncology.oxfordjournals.org/content/16/suppl_8/viii14.full.pdf+html
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/neuonc/nou222
PubMed ID:25342600

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