EGFR tyrosine kinase domain mutations in human gliomas

Marie, Yannick; Carpentier, Alexandre; Omuro, Antonio; Sanson, M; Thillet, Joëlle; Hoang-Xuân, Khê; Delattre, Jacques

doi:10.1212/01.wnl.0000158654.07080.b0

Cited by 70 publications

(50 citation statements)

References 10 publications

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“…Interpretation of correlative studies linked to these trials (Table 2) have been limited by the low number of responders and by the different techniques used (24,30,32,33). Such studies confirmed previous reports suggesting that the EGFR tyrosine kinase domain mutations that predict response to EGFR TKI in lung cancer are absent in gliomas (34,35), including in those that allegedly responded to EGFR TKI. Most studies found no correlation between outcomes and EGFR overexpression or amplification (19,24,30,33), with the exception of one study that found that tumors with high levels of EGFR expression and low levels of phosphorylated AKT/protein kinase B (pAKT) were more likely to respond than those with low levels of EGFR expression and high levels of pAKT (32).…”

Section: Epidermal Growth Factor Receptorsupporting

confidence: 63%

Lessons learned in the development of targeted therapy for malignant gliomas

Omuro

Faivre

Raymond

2007

Molecular Cancer Therapeutics

179

137

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Section: Epidermal Growth Factor Receptorsupporting

confidence: 63%

Lessons learned in the development of targeted therapy for malignant gliomas

Omuro

Faivre

Raymond

2007

Molecular Cancer Therapeutics

179

137

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“…Although gliomas with EGFR amplification tended to respond more frequently than nonamplified tumors, this was not always the case. 27 Activating somatic mutations in the EGFR tyrosine kinase domain (exons 18-21), as found in gefitinib or erlotinib-sensitive nonsmall cell lung cancer, 34,35 appear to be a rare event in primary malignant gliomas 11,26,27,36,37 and were absent in our brain tumor xenograft models. Missense mutations in the extracellular domain of EGFR, as well as coexpression of EGFRvIII mutant and wild-type PTEN, are associated with a clinical and experimental response to anti-EGFR therapy in patients with glioblastoma and in glioblastoma cell lines.…”

Section: Discussionmentioning

confidence: 71%

EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts

Geoerger

Gaspar

Opolon

et al. 2008

Intl Journal of Cancer

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Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiationinduced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy.

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“…Furthermore, these mutations in the EGFR tyrosine kinase domain have not been found in patients with glioma (Barber et al, 2004;Rich et al, 2004a;Marie et al, 2005). Rich et al (2004a) showed that gefitinib-treated GBM patients with an event-free survival of more than 24 weeks did not harbour such EGFR point mutations .…”

Section: Discussionmentioning

confidence: 99%

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

et al. 2007

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To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mgday À1 ) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1 -36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2 -104 þ ) weeks and PFS-6 was 14.3% (95% CI 4.0 -32.7%). The median overall survival was 24.6 weeks (range 4 -104 þ ). No grade 3 -4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

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EGFR tyrosine kinase domain mutations in human gliomas

Cited by 70 publications

References 10 publications

Lessons learned in the development of targeted therapy for malignant gliomas

Lessons learned in the development of targeted therapy for malignant gliomas

EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

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