Targeting EGFR in Esophagogastric Cancer

Maron, Steven Brad; Xu, James R; Janjigian, Yelena Y.

doi:10.3389/fonc.2020.553876

Cited by 11 publications

(8 citation statements)

References 62 publications

(101 reference statements)

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“…Interestingly, many of the repositioned drugs target specific pathways; EGFR (Erlotinib, Crizotinib, and Lapatinib), estrogen signalling (Tamoxifen, Fulvestrant, Hydrocortisone, and Anastrozole) and TRAIL-mediated apoptosis (Azithromycin and Anastrozole) pathways, suggesting that these pathways are key drivers of ESCC. This is in line with previous research which identified the EGFR AND ER pathways as drivers of ESCC oncogenesis and metastasis and have also been associated with patient outcome ( Maron et al, 2020 ). Crucially, some of these drugs have been shown to have therapeutic potential in vitro .…”

Section: Discussionsupporting

confidence: 92%

Drug repositioning for esophageal squamous cell carcinoma

Bennett

Huang

et al. 2022

Front. Genet.

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Esophageal cancer (EC) remains a significant challenge globally, having the 8th highest incidence and 6th highest mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common form of EC in Asia. Crucially, more than 90% of EC cases in China are ESCC. The high mortality rate of EC is likely due to the limited number of effective therapeutic options. To increase patient survival, novel therapeutic strategies for EC patients must be devised. Unfortunately, the development of novel drugs also presents its own significant challenges as most novel drugs do not make it to market due to lack of efficacy or safety concerns. A more time and cost-effective strategy is to identify existing drugs, that have already been approved for treatment of other diseases, which can be repurposed to treat EC patients, with drug repositioning. This can be achieved by comparing the gene expression profiles of disease-states with the effect on gene-expression by a given drug. In our analysis, we used previously published microarray data and identified 167 differentially expressed genes (DEGs). Using weighted key driver analysis, 39 key driver genes were then identified. These driver genes were then used in Overlap Analysis and Network Analysis in Pharmomics. By extracting drugs common to both analyses, 24 drugs are predicted to demonstrate therapeutic effect in EC patients. Several of which have already been shown to demonstrate a therapeutic effect in EC, most notably Doxorubicin, which is commonly used to treat EC patients, and Ixazomib, which was recently shown to induce apoptosis and supress growth of EC cell lines. Additionally, our analysis predicts multiple psychiatric drugs, including Venlafaxine, as repositioned drugs. This is in line with recent research which suggests that psychiatric drugs should be investigated for use in gastrointestinal cancers such as EC. Our study shows that a drug repositioning approach is a feasible strategy for identifying novel ESCC therapies and can also improve the understanding of the mechanisms underlying the drug targets.

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Section: Discussionsupporting

confidence: 92%

Drug repositioning for esophageal squamous cell carcinoma

Bennett

Huang

et al. 2022

Front. Genet.

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“…However, the impact of pathogenic PTPRT mutations in GEA requires further investigation. Finally, alterations in other GEA-associated genes were seen at high frequency in our cohort, including TP53 , EGFR , CDKN2A , SMAD4 , and ARID1A , but were not significantly enriched among BrM samples specifically. Of note, enrichment in TP53 alterations has been observed in BrM from breast carcinoma, whereas enrichment in EGFR and CDKN2A alterations has been found in BrM from lung adenocarcinoma …”

Section: Discussionmentioning

confidence: 61%

Outcomes and Molecular Features of Brain Metastasis in Gastroesophageal Adenocarcinoma

et al. 2022

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“…Recent studies have shown that EGFR is abnormally over-expressed in metastatic SACC and is a key regulatory molecule for SACC metastasis [40]. Prior studies have targeted the EGFR pathway via numerous therapeutic agents including ge tinib [41], cetuximab [42], and lapatinib [43] without meaningful response rates. In this study, we investigated the combined treatment potential targeting Meg8 and EGFR.…”

Section: Discussionmentioning

confidence: 99%

TAMs-derived exosomal Meg8 promotes the EMT and metastasis of SACC by regulating EGFR through sponge absorption of miR-148a-3p

Gao,

Wang,

Shi

et al. 2024

Preprint

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Tumor-associated macrophages (TAMs) infiltrate extensively in salivary adenoid cystic carcinoma (SACC) tissues. Our previous study found that TAMs were significantly associated with the tumor metastasis and poor patients’ prognosis. However, the role and molecular mechanism of TAMs in SACC metastasis are still to be elucidated. Present study found that TAMs-derived exosomes can be internalized by SACC cells, initiating the epithelial-mesenchymal transition (EMT) process of SACC cells. TAMs-derived exosomal RNA sequencing and metastasis-related SACC tissues RNA sequencing suggested that Lnc-Meg8 was involved in TAMs-SACC interaction. RNA fluorescent in situ hybridization, RNA immunoprecipitation, and other in vitro assays revealed that TAMs-derived exosomes transferred Lnc-Meg8 to SACC cells, which promoted EGFR expression via sponge absorption of miR-148a-3p, thus promoting the EMT process of SACC cells. In vivo fluorescence imaging and immunohistochemical staining confirmed that inhibition of TAMs-derived exosomal Meg8 significantly improved the therapeutic efficacy of EGFR inhibitor cetuximab on the EMT and metastasis of SACC cells. In summary, our results demonstrated that the TAMs-derived exosomes promoted the EMT process of SACC cells via the Lnc-Meg8/miR-148a-3p/EGFR molecular axis. Blocking exosomal Lnc-Meg8 of TAMs may be a potential therapeutic strategy for SACC.

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Targeting EGFR in Esophagogastric Cancer

Cited by 11 publications

References 62 publications

Drug repositioning for esophageal squamous cell carcinoma

Drug repositioning for esophageal squamous cell carcinoma

Outcomes and Molecular Features of Brain Metastasis in Gastroesophageal Adenocarcinoma

TAMs-derived exosomal Meg8 promotes the EMT and metastasis of SACC by regulating EGFR through sponge absorption of miR-148a-3p

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