Overexpression of wildtype EGFR is tumorigenic and denotes a therapeutic target in non-small cell lung cancer

Xu, Naiqing; Fang, Wenfeng; Mu, Libing; Tang, Yanna; Gao, Lei; Ren, Shengxiang; Cao, Dengfeng; Zhou, Lixin; Zhang, Aiqun; Liu, Deruo; Zhou, Caicun; Wong, Kwok-Kin; Yu, Lei; Zhang, Li; Chen, Liang

doi:10.18632/oncotarget.6461

Cited by 36 publications

(30 citation statements)

References 45 publications

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“…At the same time, ligand binding also promotes the internalization of EGFR and it subsequently sorted into intraluminal vesicles and directed to late endosomes and lysosomes for degradation, terminating EGFR activation . EGFR overexpression or overactivity has been found in a variety of carcinomas . Our previous study indicated that a mucin‐like membrane glycoprotein CD24 could maintain EGFR content via reducing EGFR internalization and degradation .…”

Section: Discussionmentioning

confidence: 99%

MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation

et al. 2017

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Section: Discussionmentioning

confidence: 99%

MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation

et al. 2017

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“…Its ligands, EGF and transforming growth factor-α, bind to the ectodomain of EGFR to elicit biological effects through the RAS/RAF/mitogen-activated protein kinase kinase 1/extracellular signal-related kinase pathway, the phosphoinositide 3-kinase/AKT pathway, the phospholipase-Cγ/protein kinase C pathway, the SRC/signal transducer and activator of transcription pathway and the corresponding crosstalk, leading to the regulation of cellular proliferation, survival, apoptosis, invasion and metastasis (11,12). The overexpression of EGFR usually indicates rapid progress, resistance to chemoradiotherapy and a poor prognosis for patients with lung cancer (13,14). Various small-molecule tyrosine kinase inhibitors (TKIs) and anti-EGFR antibodies targeting EGFR have been developed over the previous 30 years.…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of nimotuzumab in combination with cisplatin in lung cancer cell line A549 inï¿½vitro

Yang

Zhou

et al. 2018

Oncol Lett

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Abstract. Nimotuzumab, a humanized IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR), increases radiosensitivity in lung cancer. Cisplatin is an effective antitumor agent in lung cancer. In the present study, the antitumor activity of nimotuzumab combined with cisplatin was investigated in A549 lung cancer cells. Viability, cell cycle distribution and cyclin D1 expression were assessed following treatment with nimotuzumab alone, cisplatin alone, nimotuzumab in combination with cisplatin, and nimotuzumab followed sequentially by cisplatin. The inhibitory effect on cell viability of nimotuzumab sequentially followed by cisplatin was higher compared with cisplatin alone (82.17±1.62 vs. 56.97±1.42%). Compared with treatment by cisplatin alone, cell cycle analysis by flow cytometry demonstrated that the percentage of cells in the G 0 /G 1 phase was increased when A549 cells were treated with nimotuzumab followed sequentially by cisplatin (P<0.01). However, the proportion of cells in G 0 /G 1 phase was decreased when A549 cells were treated with nimotuzumab and cisplatin simultaneously compared with cisplatin alone (P<0.05). Cyclin D1 expression was decreased in all chemotherapy treatment groups; the most significant decrease was in A549 cells treated with nimotuzumab followed sequentially by cisplatin. Nimotuzumab may enhance the antitumor activity of cisplatin on A549 cells. The cell cycle arrest at G 0 /G 1 observed may have been due to decreased cyclin D1 levels. Potential antagonism was identified when A549 cells were treated with nimotuzumab and cisplatin simultaneously, indicating that targeted therapy may be more effective when administered prior to conventional chemotherapy. IntroductionLung cancer has been the most common cancer worldwide, and the leading cause of cancer-associated mortality, since 1985 (1). The 5-year survival rate for lung carcinoma overall is poor, at 16-17% (2). Surgery is not suitable for the majority of patients with lung cancer, as diagnoses are often obtained at advanced disease stages. The standard of care for advanced non-small cell lung cancer (NSCLC) is cisplatin in combination with 1 to 3 of the following drugs: Paclitaxel, gemcitabine and docetaxel (3). The efficacy of chemotherapy is limited due to its side effects and the lack of response in certain sub-populations of patients. Research efforts have focused on identifying molecular targets and developing molecular-targeted therapies based on the understanding of the molecular abnormalities associated with lung cancer (4-6).Insight into the pathobiology of NSCLC has facilitated the development of targeted molecular therapies that target specific mutations that serve critical roles in the progression to aggressive disease. Mutations in the epidermal growth factor receptor (EGFR), KRAS and anaplastic lymphoma kinase (ALK) genes are mutually exclusive in patients with NSCLC, and targeted therapy may be affected due to the existence of one mutation in lieu of another. Therefore, the detection of these mutati...

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“…Lung cancer is the leading cause of cancer death in both men and women worldwide, accounting for over a million deaths annually [ 1 , 2 ]. Epidermal growth factor receptor (EGFR), a member of the c-erbB family, is highly expressed in a variety of human tumors, including non-small cell lung cancer (NSCLC), and is implicated in tumor development [ 3 , 4 ]. EGFR overexpression could be a result of gene amplification, enhanced transcription, or change in protein metabolic turnover [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer

Wen

Ling

et al. 2016

Oncotarget

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The migration and invasion inhibitory protein (MIIP) has been discovered recently to have inhibitory functions in cell proliferation and migration. Overexpression of MIIP reduced the intracellular steady-state level of epidermal growth factor receptor (EGFR) protein in lung cancer cells with no effect on EGFR mRNA expression compared to that in the control cells. This MIIP-promoted EGFR protein degradation was reversed by proteasome and lysosome inhibitors, suggesting the involvement of both proteasomal and lysosomal pathways in this degradation. This finding was further validated by pulse-chase experiments using 35S-methionine metabolic labeling. We found that MIIP accelerates EGFR protein turnover via proteasomal degradation in the endoplasmic reticulum and then via the lysosomal pathway after its entry into endocytic trafficking. MIIP-stimulated downregulation of EGFR inhibits downstream activation of Ras and blocks the MEK signal transduction pathway, resulting in inhibition of cell proliferation. The negative correlation between MIIP and EGFR protein expression was validated in lung adenocarcinoma samples. Furthermore, the higher MIIP protein expression predicts a better overall survival of Stage IA-IIIA lung adenocarcinoma patients who underwent radical surgery. These findings reveal a new mechanism by which MIIP inhibits cell proliferation.

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Overexpression of wildtype EGFR is tumorigenic and denotes a therapeutic target in non-small cell lung cancer

Cited by 36 publications

References 45 publications

MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation

MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation

Antitumor activity of nimotuzumab in combination with cisplatin in lung cancer cell line A549 inï¿½vitro

MIIP accelerates epidermal growth factor receptor protein turnover and attenuates proliferation in non-small cell lung cancer

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