The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies

Ji, Hongbin; Li, Danan; Chen, Liang; Shimamura, Takeshi; Kobayashi, Susumu; McNamara, Kate; Mahmood, Umar; Mitchell, Aaron P.; Sun, Yangping; Al-Hashem, Ruqayyah; Chirieac, Lucian R.; Padera, Robert F.; Bronson, Roderick T.; Kim, William; Jänne, Pasi A.; Shapiro, Geoffrey I.; Tenen, Daniel G.; Johnson, Bruce E.; Weissleder, Ralph; Sharpless, Norman E.; Wong, Kwok-Kin

doi:10.1016/j.ccr.2006.04.022

Cited by 412 publications

(345 citation statements)

References 45 publications

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“…Before imaging, oxygen scavenging solution was replaced with an imaging buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM NaCl, 10% (w/v) glucose, 0.5 mg/ml glucose oxidase (Sigma-Aldrich), 40 µg/ml catalase (Sigma-Aldrich) and 1% (v/v) β-mercaptoethanol [48]. For the fixed samples, H&E staining was performed for detection of histology; Immunostaining of phosphorylated EGFR (pY1173, diluted at 1:70 ratio by 3% BSA) was done as previously described [49].…”

Section: Human Specimen Primary Cell Isolation and Pretreatmentmentioning

confidence: 99%

Regulation of EGFR nanocluster formation by ionic protein-lipid interaction

et al. 2014

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The abnormal activation of epidermal growth factor receptor (EGFR) is strongly associated with a variety of human cancers but the underlying molecular mechanism is not fully understood. By using direct stochastic optical reconstruction microscopy (dSTORM), we find that EGFR proteins form nanoclusters in the cell membrane of both normal lung epithelial cells and lung cancer cells, but the number and size of clusters significantly increase in lung cancer cells. The formation of EGFR clusters is mediated by the ionic interaction between the anionic lipid phosphatidylinositol-4,5-bisphosphate (PIP2) in the plasma membrane and the juxtamembrane (JM) region of EGFR. Disruption of EGFR clustering by PIP2 depletion or JM region mutation impairs EGFR activation and downstream signaling. Furthermore, JM region mutation in constitutively active EGFR mutant attenuates its capability of cell transformation. Collectively, our findings highlight the key roles of anionic phospholipids in EGFR signaling and function, and reveal a novel mechanism to explain the aberrant activation of EGFR in cancers.

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Section: Human Specimen Primary Cell Isolation and Pretreatmentmentioning

confidence: 99%

Regulation of EGFR nanocluster formation by ionic protein-lipid interaction

et al. 2014

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“…Two groups of researchers have recently developed transgenic mice that express either exon 19 deletion mutant or the L858R mutant in type II pneumocytes under the control of doxycycline (Ji et al, 2006;Politi et al, 2006). Expression of either EGFR mutant leads to the development of adenocarcinoma similar to human bronchioloalveolar cell carcinoma and withdrawal of doxycycline to reduce expression of transgene or erlotinib treatment resulted in tumour regression.…”

Section: Egfr Mutationsmentioning

confidence: 99%

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Uramoto

Mitsudomi

2007

Br J Cancer

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Subsets of patients with non-small cell lung cancer respond remarkably well to small molecule tyrosine kinase inhibitors (TKI) specific for epidermal growth factor receptor (EGFR) such as gefitinib or erlotinib. In 2004, it was found that EGFR mutations occurring in the kinase domain are strongly associated with EGFR-TKI sensitivity. However, subsequent studies revealed that this relationship was not perfect and various predictive markers have been reported. These include EGFR gene copy numbers, status of ligands for EGFR, changes in other HER family genes or molecules downstream to EGFR including KRAS or AKT. In this review, we would like to review current knowledge of predictive factors for EGFR-TKI. As all but one phase III trials failed to show a survival advantage of the treatment arm involving EGFR-TKIs, it is necessary to select patients by these biomarkers in future clinical trials. Through these efforts, it would be possible to individualise EGFR-TKI treatment for patients suffering from lung cancer.

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“…Epidermal growth factor receptor (EGFR) is a type of receptor tyrosine kinase, and it has been reported that EGFR mutations are mainly concentrated in exons 19 and 21 (Ji et al, 2006;Lim et al, 2014;Liam et al, 2014). After epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment, the signaling through Zhong-Ming Yang 1,2 , Xian-Ping Ding 1 *, Lei Pen 2 , Lin Mei 2 , Ting Liu 2 this pathway is blocked, leading to tumor cell necrosis.…”

Section: Introductionmentioning

confidence: 99%

Analysis of CEA Expression and EGFR Mutation Status in Non-small Cell Lung Cancers

Yang¹,

Ding²,

Pen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: The serum carcinoembryonic antigen (CEA) level can reflect tumor growth, recurrence and metastasis. It has been reported that epidermal growth factor receptor (EGFR) mutations in exons 19 and 21may have an important relationship with tumor cell sensitivity to EGFR -TKI therapy. In this study, we investigated the clinical value of EGFR mutations and serum CEA in patients with non-small cell lung cancer (NSCLC). Materials and Methods:The presence of mutations in EGFR exons 19 and 21 in the tissue samples of 315 patients with NSCLC was detected with real-time fluorescent PCR technology, while the serum CEA level in cases who had not yet undergone surgery, radiotherapy, chemotherapy and targeted therapy were assessed by electrochemical luminescence. Results: The mutation rates in EGFR exons 19 and 21 were 23.2% and 14.9%, respectively, with the two combined in 3.81%. Measured prior to the start of surgery, radiotherapy, chemotherapy and targeted treatment, serum CEA levels were abnormally high in 54.3% of the patients. In those with a serum CEA level <5 ng/mL, the EGFR mutation rate was 18.8%, while with 5~19 ng/mL and ≥20 ng/mL, the rates were 36.4% and 62.5%. In addition, in the cohort of patients with the CEA level being 20~49 ng/mL, the EGFR mutation rate was 85.7%, while in those with the CEA level ≥50 ng/mL, the EGFR mutation rate was only 20.0%, approximately the same as in cases with the CEA level<5 ng/mL. Conclusions: There is a positive correlation between serum CEA expression level and EGFR mutation status in NSCLC patients, namely the EGFR mutation-positive rate increases as the serum CEA expression level rises within a certain range (≥20 ng/mL, especially 20~49 ng/mL). If patient samples are not suitable for EGFR mutation testing, or cannot be obtained at all, testing serum CEA levels might be a simple and easy screening method. Hence, for the NSCLC patients with high serum CEA level (≥20 ng/mL, especially 20~49 ng/mL), it is worthy of attempting EGFR-TKI treatment, which may achieve better clinical efficacy and quality of life.

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The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies

Cited by 412 publications

References 45 publications

Regulation of EGFR nanocluster formation by ionic protein-lipid interaction

Regulation of EGFR nanocluster formation by ionic protein-lipid interaction

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Analysis of CEA Expression and EGFR Mutation Status in Non-small Cell Lung Cancers

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