Mechanisms of resistance to EGFR targeted therapies

Hrustanovic, Gorjan; Lee, Bianca J.; Bivona, Trever G.

doi:10.4161/cbt.23627

Cited by 49 publications

(48 citation statements)

References 128 publications

(154 reference statements)

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“…17 EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib show anti-tumor activity in patients with advanced non-small cell lung cancer, however, there are clinical problems in that EGFR-TKIs have a limited degree of benefit to patients with a non mutant EGFR and patients with a mutant EGFR develop disease progression by acquiring resistance. 18,19 In the present study, we found that SP-D downregulated EGF signaling and (Fig. 1A, right panel).…”

Section: Introductionmentioning

confidence: 56%

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

et al. 2014

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Section: Introductionmentioning

confidence: 56%

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

et al. 2014

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“…Growing evidence show that activation of AKT and ERK1/2 is critical for survival and proliferation driven by EGFR signals, either activated by EGFR ligands or activating EGFR mutations, in NSCLC [28,29]. EGFR tyrosine kinase inhibitors (TKIs) are effective in treatment of lung cancer with activating EGFR mutations and currently the standard treatment option for advanced NSCLC; however, often resistance to TKIs develops within months after the start of treatment [34,36]. TKIs alone have limited effect on NSCLC with wild type EGFR [35,37] and dual inhibition of EGFR and AKT is required to induce apoptosis and inhibit growth of EGFR wild type NSCLC cells [38,39].…”

Section: Discussionmentioning

confidence: 99%

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

Yan¹,

Shen²,

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer is one of the most prevalent malignancies in the world. The 5-year survival rate for non-small cell lung cancer (NSCLC) patients is only approximately 15%, with metastasis as the primary cause of death. This study was aimed to investigate cytotoxic effect of external qi of Yan Xin Qigong (YXQ-EQ) toward human lung adenocarcinoma A549 cells as well as its effect on signaling pathways promoting migration, invasion and epithelial-to-mesenchymal transition (EMT) in A549 cells. Methods: Cytotoxic effect of YXQ-EQ was evaluated using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] and cologenic assays. Apoptosis of treated cells was determined by Annexin V/propidium iodide staining and flow cytometry analysis, while cell migration and invasion were determined using transwell assays and EMT was assessed by morphological changes in cells. Protein expression and phosphorylation were examined by immunoblot analyses. Results: YXQ-EQ induced apoptosis in A549 cells, resulting in a pronounced reduction in viability and clonogenic formation. This was associated with inhibition of phosphorylation of AKT and ERK1/2 and reduced expression of anti-apoptotic proteins BCL-xL, XIAP and survivin. Furthermore, YXQ-EQ inhibited EGF/EGFR signaling and EGF mediated migration and invasion of A549 cells. While TGF-β1 induced phosphorylation of SMAD2/3 and EMT in A549 cells, YXQ-EQ suppressed TGF-β/SMAD signaling and induced cell death in these cells in the presence of TGF-β1. Conclusion: Our findings suggest that YXQ-EQ could exert anti-lung cancer effects via inhibiting signaling pathways that are important for NSCLC cell survival and NSCLC metastasis.

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“…In most cases, EGFR mutations are involved in the development of tumor resistance against traditional EGFR-targeted drugs, and can lead to proliferation signaling of cancer cells independent of EGF binding [13,14]. The precondition of pLLO-hEGF applied in antitumor therapy is that it cannot accelerate cancer cell proliferation due to its “EGF tail”.…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms of tumor tolerance to EGFR inhibitors involve the cross-talk between different oncogenic signal pathways and the “loss of function” mutation of EGFR [12,13]. EGFR-activating mutations that target the kinase catalytic domain abrogate autoinhibition and result in significant increase in kinase activity [14]. In either “increased activity” or “loss of function” case, the role of EGF interacting with EGFR during the oncogenic signaling transduction is weakened and even abolished.…”

Section: Introductionmentioning

confidence: 99%

Cloning and Expression of a Novel Target Fusion Protein and its Application in Anti-Tumor Therapy

Sun

Zhu

Feng

et al. 2015

Cell Physiol Biochem

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Backgrounds: Epidermal growth factor (EGF) is a 53 amino acid polypeptide and its receptor EGFR is an established therapeutic target for anti-tumor therapy. Two major categories of EGFR-targeted drugs include monoclonal antibodies (mAbs) and small molecular tyrosine kinase inhibitors (TKIs). However, drug resistance occurs in a significant proportion of patients due to EGFR mutations. Since EGFR can maintain activation while abrogating the activity of mAbs or TKIs, or bypass signaling functions while successfully circumventing the EGF-EGFR switch, developing new mechanism-based inhibitors is necessary. Methods: In this study, based on the principle of tumor immunotherapy, a recombinant protein pLLO-hEGF was constructed. The N-terminal portion contains three immunodominant epitopes from listeriolysin O (LLO) and the C-terminal includes EGF. To use EGF as a target vector to recognize EGFR-expressing cancer cells, immunodominant epitopes could enhance immunogenicity of tumor cells for immune cell activation and attack. Results: Recombinant protein pLLO-hEGF was successfully expressed and showed strong affinity to cancer cells. Also, pLLO-hEGF could significantly stimulate human lymphocyte proliferation and the lymphocytes demonstrated enhanced killing potency in EGFR-expressing cancer cells in vitro and in vivo. Conclusion: This study can provide novel strategies and directions in tumor biotherapy.

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Mechanisms of resistance to EGFR targeted therapies

Cited by 49 publications

References 128 publications

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

YXQ-EQ Induces Apoptosis and Inhibits Signaling Pathways Important for Metastasis in Non-Small Cell Lung Carcinoma Cells

Cloning and Expression of a Novel Target Fusion Protein and its Application in Anti-Tumor Therapy

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