Resistance to Cetuximab in EGFR-Overexpressing Esophageal Squamous Cell Carcinoma Xenografts Due to FGFR2 Amplification and Overexpression

Zhang, Yi; Pan, Tiecheng; Zhong, Xiaoxuan; Cheng, Can

doi:10.1254/jphs.14150fp

Cited by 10 publications

(9 citation statements)

References 22 publications

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“…In esophageal cancer, resistance to EGFRi is associated with fibroblast growth factor receptor 2 (FGFR2) amplification and overexpression. 74 In NSCLC, the amplification of hepatocyte growth factor receptor (c-MET) has been implicated in resistance to EGFR kinase inhibition by reactivating ErbB signaling through the ErbB3 receptor. 75 Studies in NSCLC also suggest the Axl receptor can facilitate resistance to erlotinib.…”

Section: Potential Mechanisms Of Inherent Resistance To Egfri In Metamentioning

confidence: 99%

The paradoxical functions of EGFR during breast cancer progression

Ali

Wendt

2017

Sig Transduct Target Ther

117

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The epidermal growth factor receptor (EGFR) is one of the most well-studied signaling pathways in cancer progression. As a result, numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver. Several of these EGFR inhibitors (EGFRi) have been evaluated in metastatic breast cancer, as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis. Surprisingly, these trials have been unanimously unsuccessful at improving patient outcomes. Numerous factors, such as lack of proper patient selection may have contributed to the failure of these trials. However, recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion, dissemination and ultimate metastasis of breast cancer cells. Herein, we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting. Overall, we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors, a process we term the ‘EGFR paradox,’ contribute to the clinically observed inherent resistance to EGFRi. Furthermore, this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.

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Section: Potential Mechanisms Of Inherent Resistance To Egfri In Metamentioning

confidence: 99%

The paradoxical functions of EGFR during breast cancer progression

Ali

Wendt

2017

Sig Transduct Target Ther

117

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“…Inhibition of FGFR2 signaling restored its sensitivity to cetuximab. The antitumor effect may be attributed to inhibition of AKT phosphorylation (8). Although FGFR amplification, mutation, and fusion are the main mechanisms mediating FGFR activation FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial-mesenchymal transition to gefitinib and promoting solid tumor development (9,10), tyrosine phosphorylation of FGFR plays a key role in enhancing the activity of the protein.…”

Section: Introductionmentioning

confidence: 99%

FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

et al. 2018

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Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK‑8 assay, flow cytometry and western blotting assays. Twenty‑six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p‑FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p‑FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9±2.1 and 4.13±0.12 µM in TE10 cells, and 9.85±5.5 and 3.21±0.76 µM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p‑FGFR1 and p‑AKT than that in EC9706 cells. AZD4547 and gefitinib co‑treatment resulted in a significant decrease in the level of p‑AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib.

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“…In the current study, we generated an in vivo PHA665752-resistant xenograft model by using a protocol similar to Yi et al’s study. 14 Gene profiles of PHA665752-sensitive and -resistant tumor tissues were then compared with RNA-seq. The results showed that overexpression of gene PI3K p110α would be found in the resistant tumor tissues but not in the sensitive ones.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

Liu²,

et al. 2015

DDDT

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Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α’s biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer.

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Resistance to Cetuximab in EGFR-Overexpressing Esophageal Squamous Cell Carcinoma Xenografts Due to FGFR2 Amplification and Overexpression

Cited by 10 publications

References 22 publications

The paradoxical functions of EGFR during breast cancer progression

The paradoxical functions of EGFR during breast cancer progression

FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

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Resistance to Cetuximab in EGFR-Overexpressing Esophageal Squamous Cell Carcinoma Xenografts Due to FGFR2 Amplification and Overexpression

Cited by 10 publications

References 22 publications

The paradoxical functions of EGFR during breast cancer progression

The paradoxical functions of EGFR during breast cancer progression

FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

Overexpression of PI3K p110&alpha; contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

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Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts