Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy

Kancha, Rama Krishna; Bubnoff, Nikolas von; Peschel, Christian; Duyster, Justus

doi:10.1158/1078-0432.ccr-08-1757

Cited by 146 publications

(138 citation statements)

References 35 publications

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“…2) EGFR mutation was described previously in a non-small-cell lung carcinoma and was suggested to respond to EGFR TKI (18). For the other EGFR TK domain mutation (p.866EOK) found in our study, unresponsiveness upon EGFR TKI treatment was described (19).…”

Section: Discussionsupporting

confidence: 61%

Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

Hermsen

Haak

Krijger

et al. 2013

European Journal of Endocrinology

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Background: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.The epidermal growth factor receptor (EGFR) has been implicated in the development of one-third of all malignancies. EGFR pathway members in ACC have been investigated, however, without available clinical data and relation to survival. Methods: In this study, mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue. Results: One BRAF, two EGFR TK domain (c.2590GOA, p.864AOT) and 11 TP53, but no PIK3CA or KRAS, mutations were found. No relationship was found between mutation status, immunostaining and mitotane response or survival. Conclusion: In conclusion, our data suggest that the role of EGFR tyrosine kinase inhibitors in ACC is limited. Treatment with EGFR monoclonal antibodies on the other hand might be beneficial for a larger group of patients. The possible efficacy of this therapy in ACC should be evaluated in future trials.

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Section: Discussionsupporting

confidence: 61%

Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

Hermsen

Haak

Krijger

et al. 2013

European Journal of Endocrinology

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“…Similarly, in the present study, the KYSE270 cell line with an EGFR L861Q mutation was hypersensitive to afatinib. This is consistent with several previous studies showing that this mutation is an activating oncogenic mutation (16,33,34). This cell line, however, was not sensitive to erlotinib, a reversible EGFR inhibitor.…”

Section: Discussionsupporting

confidence: 93%

“…This cell line, however, was not sensitive to erlotinib, a reversible EGFR inhibitor. Previous studies have shown that reversible EGFR-TKIs are less effective and irreversible EGFR-TKIs are more effective against cells carrying the EGFR L861Q mutation (33,34,37,38), which is compatible with our data. Furthermore, our study has shown that the SAS cell line with the HER4 G1109C mutation is sensitive to afatinib, which also has an inhibitory effect on HER4, and that this mutation is an activating mutation with a transformational ability and tumorigenicity.…”

Section: Discussionsupporting

confidence: 93%

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Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.

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“…Non-small cell lung cancers, and particularly the NSCLC adenocrcinoma subtype, are one of the main causes of human lethality [15,16], and the molecular mechanisms underlying its progression are still poorly understood. The therapies targeting well known pathways, such as the EGFR pathway [1,2,3,17], were shown to be effective for only a small fraction of NSCLC tumors. A very few reports show a role for specific genes, such as EML4-ALK [4] or CRK [18], in lung adenocarcinoma progression, and they do not clarify the corresponding pathways.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Growth Control Network Specific for Human Lung Adenocarcinoma Cells

Pinna

Zinovyev

Araujo

et al. 2012

Math. Model. Nat. Phenom.

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Abstract. Many cancer-associated genes and pathways remain to be identified in order to clarify the molecular mechanisms underlying cancer progression. In this area, genome-wide lossof-function screens appear to be powerful biological tools, allowing the accumulation of large amounts of data. However, this approach currently lacks analytical tools to exploit the data with maximum efficiency, for which systems biology methods analyzing complex cellular networks may be extremely helpful. In this article we report such a systems biology strategy based on the construction of a Network for a biological process and specific for a given cell system (cell type). The networks are created from genome-wide loss-of-function screen datasets. We also propose tools to analyze network properties. As one of the tools, we suggest a mathematical model for discrimination between two distinct cell processes that may be affected by knocking down the activity of a gene, i. e., a decreased cell number may be caused by arrested cell proliferation or enhanced cell death. Next we show how this discrimination between the two cell processes helps to construct two corresponding subnetworks. Finally, we demonstrate an application of the proposed strategy to the identification and characterization of putative novel genes and pathways significant for the control of lung cancer cell growth, based on the results of a genome-wide proliferation/viability loss-of-function screen of human lung adenocarcinoma cells.

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Functional Analysis of Epidermal Growth Factor Receptor (EGFR) Mutations and Potential Implications for EGFR Targeted Therapy

Cited by 146 publications

References 35 publications

Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Analysis of the Growth Control Network Specific for Human Lung Adenocarcinoma Cells

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