Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial

Hegi, Monika E.; Diserens, Annie‐Claire; Bady, Pierre; Kamoshima, Yuta; Kouwenhoven, Mathilde C.M.; Delorenzi, Mauro; Lambiv, Wanyu L.; Hamou, Marie‐France; Matter, Matthias S.; Koch, Arend; Heppner, Frank L.; Yonekawa, Yasuhiro; Merlo, Adrian; Frei, Karl; Mariani, Luigi; Höfer, Silvia

doi:10.1158/1535-7163.mct-11-0048

Cited by 173 publications

(118 citation statements)

References 36 publications

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“…It also participates in drug and radiotherapy resistance via stimulation of different pathways such as Ras-Raf-ERK and PI3K-AKT-mTOR (3). However, although first-generation EGFR tyrosine-kinase inhibitors (TKIs) such as erlotinib and gefitinib have been proven to be active in the treatment of lung cancer, they have produced poor results in glioma patients (4) and were not able to inhibit EGFR signaling in vivo (5). Nevertheless it has been estimated that the EGFR gene is amplified in 30% to 40% of GBMs and nearly 50% of them overexpress the receptor, whereas this alteration is infrequent in anaplastic astrocytoma or in secondary GBMs (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Zahonero

Aguilera

Ramírez-Castillejo

et al. 2015

Molecular Cancer Therapeutics

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Glioblastomas (GBM) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first-generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here, we have tested the antitumoral efficacy of a second-generation inhibitor, dacomitinib (PF299804, Pfizer), that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal, and proliferation in EGFR-amplified AE EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR-amplified cell lines, with a decrease in the expression of stem cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirm that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN-deleted GBM line). Dacomitinib is being tested in second line for EGFR-amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs. Mol Cancer Ther; 14(7); 1548-58. Ó2015 AACR.

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Section: Introductionmentioning

confidence: 99%

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Zahonero

Aguilera

Ramírez-Castillejo

et al. 2015

Molecular Cancer Therapeutics

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“…To date, clinical trials targeting EGFR signaling in patients with glioblastoma with tyrosine kinase inhibitors (erlotinib or gefitinib) or an anti-EGFR antibody (cetuximab) have, however, largely been disappointing (10,11). Potential reasons include as follows: (i) insufficient penetration of agents into the tumor, (ii) insufficient target inhibition, (iii) limited dependence of tumor cells on EGFR pathway signaling, (iv) compensatory activation of other pathways, (v) paradoxic protection of tumor cells against stress via reduction of energy consumption through EGFR signaling inhibition, and (vi) cellular heterogeneity, that is, only a subfraction of tumor cells displays EGFR amplification and/or EGFRvIII expression (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma Stem–like Cell Lines with Either Maintenance or Loss of High-Level EGFR Amplification, Generated via Modulation of Ligand Concentration

Schulte

Günther

Martens

et al. 2012

Clinical Cancer Research

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Purpose: Despite the high incidence of epidermal growth factor receptor (EGFR) gene amplification and rearrangement in glioblastomas, no suitable cell line exists that preserves these alterations in vitro and is tumorigenic in immunocompromised mice. On the basis of previous observations that glioblastoma cells cultured with serum lose the EGFR amplification rapidly and that EGF can inhibit the growth of EGFRamplified tumor cells, we hypothesized that serum-free and EGF-free culture conditions could promote maintenance of the EGFR amplification.Experimental Design: Cells from EGFR-amplified glioblastomas were taken into culture using neural stem cell conditions with modifications, including varying oxygen concentrations and omission of routine EGF supplementation.Results: High-level EGFR amplification was rapidly lost in 5 glioblastoma cultures supplemented with EGF, whereas it was preserved in cultures from the same tumors established without EGF. Cultures from 2 glioblastomas developed into pairs of cell lines, with either stable maintenance or irreversible loss of highlevel EGFR amplification in the majority of cells. One EGFR-amplified cell line preserved expression of the receptor variant EGFRvIII. Cell lines with high-level EGFR amplification/EGFRvIII expression formed highly aggressive tumors in nude mice, whereas nonamplified cell lines were either nontumorigenic or grew significantly more slowly. In contrast, nonamplified cell lines proliferated faster in vitro. All cell lines responded to erlotinib, with inhibition of receptor activation and proliferation but partly different effects on downstream signaling and migration.Conclusions: Isogenic glioblastoma cell lines maintaining stable differences in EGFR/EGFRvIII status can be derived by varying exposure to EGF ligand and reflect the intratumoral genetic heterogeneity. Clin Cancer Res; 18(7); 1901-13. Ó2012 AACR.

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“…The high prevalence of EGFR and PDGFRA alterations seen in GBM has nominated these RTKs as priority candidates for therapeutic targeting. However, clinical trials of small-molecule inhibitors targeting EGFR and PDGFR used as single therapy have shown little response in unselected patients, and amplification status of the receptors has not yet been found to be predictive (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response

Szerlip

Pedraza

Chakravarty

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

471

396

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Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases (RTKs). Although most GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly plateletderived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.glioma | glioblastoma genetics | mosaicism | amplicon

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Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial

Cited by 173 publications

References 36 publications

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma

Glioblastoma Stem–like Cell Lines with Either Maintenance or Loss of High-Level EGFR Amplification, Generated via Modulation of Ligand Concentration

Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response

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