The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation.

Details

Serval ID
serval:BIB_2AF864642976
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation.
Journal
Drug resistance updates
Author(s)
Saleem H., Kulsoom Abdul U., Küçükosmanoglu A., Houweling M., Cornelissen FMG, Heiland D.H., Hegi M.E., Kouwenhoven MCM, Bailey D., Würdinger T., Westerman B.A.
ISSN
1532-2084 (Electronic)
ISSN-L
1368-7646
Publication state
Published
Issued date
03/2019
Peer-reviewed
Oui
Volume
43
Pages
29-37
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing. We performed an exhaustive analysis of the mechanisms that might account for therapy resistance against EGFR inhibition. We define two major mechanisms of resistance and propose modalities to overcome them. The first resistance mechanism concerns target independence. In this case, cells have lost expression of the EGFR protein and experience no negative impact of EGFR targeting. Loss of extrachromosomally encoded EGFR as present in double minute DNA is a frequent mechanism for this type of drug resistance. The second mechanism concerns target compensation. In this case, cells will counteract EGFR inhibition by activation of compensatory pathways that render them independent of EGFR signaling. Compensatory pathway candidates are platelet-derived growth factor β (PDGFβ), Insulin-like growth factor 1 (IGFR1) and cMET and their downstream targets, all not commonly mutated at the time of diagnosis alongside EGFR mutation. Given that both mechanisms make cells independent of EGFR expression, other means have to be found to eradicate drug resistant cells. To this end we suggest rational strategies which include the use of multi-target therapies that hit truncation mutations (mechanism 1) or multi-target therapies to co-inhibit compensatory proteins (mechanism 2).
Keywords
Brain Neoplasms/drug therapy, Brain Neoplasms/genetics, Brain Neoplasms/pathology, Carcinogenesis/drug effects, Carcinogenesis/genetics, Drug Resistance, Neoplasm, ErbB Receptors/antagonists & inhibitors, ErbB Receptors/genetics, ErbB Receptors/metabolism, Glioblastoma/drug therapy, Glioblastoma/genetics, Glioblastoma/pathology, Humans, Molecular Targeted Therapy/methods, Mutation, Oncogenes/genetics, Protein Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/therapeutic use, Proto-Oncogene Proteins c-met/metabolism, Proto-Oncogene Proteins c-sis/metabolism, Receptor, IGF Type 1/metabolism, Signal Transduction/drug effects, Signal Transduction/genetics, Treatment Outcome, CMET, EGFR inhibition, Glioblastoma, IGFR1, Target compensation, PDGFR, Target independence, Therapy resistance
Pubmed
Web of science
Open Access
Yes
Create date
27/05/2019 16:51
Last modification date
18/02/2020 6:20
Usage data