The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Epidermal Growth Factor Receptor, Protein Kinase B/Akt, and Glioma Response to Erlotinib
Abstract
BACKGROUND: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide. METHODS: Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran-Mantel-Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided. RESULTS: Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P < .001). The level of phosphorylated PKB/Akt was also associated with time to progression (P < .001). CONCLUSIONS: Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.
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“Despite the compelling nature of EGFR as a drug target in GBM, the EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy (9–11), in large part as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases (9, 10, 12).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [10]
In the citing paper
“There is clinical evidence suggesting that the presence of EGFRvIII can predict clinical responses of GBMs to the EGFR TKIs gefitinib and erlotinib (Haas-Kogan et al., 2005; Mellinghoff et al., 2005).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Haas-Kogan et al., 2005
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Metadata
- Authors
- Haas-Kogan, D. A., Prados, M. D., Tihan, T., Eberhard, D. A., Jelluma, N., Arvold, N. D., Baumber, R., Lamborn, K. R., Kapadia, A., Malec, M., Berger, M. S., & Stokoe, D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Haas-Kogan, Daphne A.
- ORCID
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-06-15
- Volume
- 97
- Issue
- 12
- Pages
- 880-887
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2104743043
- Cited by
- 465
- References
- 37
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 13 · 2016: 6 · 2015: 17 · 2014: 24 · 2013: 27 · 2012: 34
- FWCI
- 22.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5m01rr000079-42)
- National Cancer Institute (P50CA097257)
- National Institute of Neurological Disorders and Stroke (P01NS042927, P01 NS42927)
- National Center for Research Resources (M01 RR-00079)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- erlotinib, EGFR tyrosine kinase inhibitors, high-grade glioma, glioblastoma, EGFR amplification, EGFRvIII, Akt phosphorylation, Akt, temozolomide, predictive biomarkers, treatment response, PTEN mutation, time to progression
- MeSH terms
- Erlotinib Hydrochloride, Temozolomide, Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Dacarbazine, Drug Administration Schedule, Female, Glioma, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Phosphoric Monoester Hydrolases, Phosphorylation, Proto-Oncogene Proteins, Quinazolines, Supratentorial Neoplasms, Protein Serine-Threonine Kinases, In Situ Hybridization, Fluorescence, Drug Resistance, Neoplasm, Area Under Curve, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, ErbB Receptors
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