Epidermal Growth Factor Receptor in Pancreatic Cancer

Oliveira‐Cunha, Melissa; Newman, William G.; Siriwardena, Ajith K.

doi:10.3390/cancers3021513

Cited by 134 publications

(84 citation statements)

References 51 publications

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“…c-MET-targeted therapy has been also tested in combination with EGFR TKIs 47. Of note, EGFR-targeted therapies have also been evaluated in PDAC 48. Our work shows that inhibition of DYRK1A resulted in reduced accumulation of both EGFR and c-MET proteins, and that DYRK1A and DYRK1B paralogues function similarly in this regard.…”

Section: Discussionmentioning

confidence: 70%

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Luna

Boni

Cuatrecasas

et al. 2018

Gut

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Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis.DesignWe analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity.ResultsWe showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling.ConclusionsThese findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.

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Section: Discussionmentioning

confidence: 70%

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Luna

Boni

Cuatrecasas

et al. 2018

Gut

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“…When cancer cells utilize signaling initiated by EGFRs, they establish an anti-apoptotic state within the cell as well as to upregulate mitogenic, angiogenic and pro-invasive cellular mechanisms [171]. EGFR signaling has also been linked to EMT [172].…”

Section: Role Of Neu1 Sialidase In Cancer Cell Survival and Acquired mentioning

confidence: 99%

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

2016

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Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.

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“…The EGFR is overexpressed in a variety of human tumors including pancreatic, non‐small‐cell lung cancer, breast, head and neck, gastric, colorectal, esophageal, prostate, bladder, renal and ovarian cancers (Salomon et al ., ). Overexpression of EGFR and its ligands is frequently observed in pancreatic cancer and correlates with poor prognosis, disease progression, and metastasis (Oliveira‐Cunha et al ., ; Xie and Xie, ), supporting the prominent role of the EGFR family for malignant transformation, prevention of apoptosis, and drug resistance. The pancreatic islet cell is considered by some to be a signaling hub (Barker et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpeneSO1861

et al. 2017

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Targeted cancer therapy provides the basis for the arrest of tumor growth in aggressive pancreatic carcinoma; however, a number of protein‐based targeted toxins lack efficacy due to insufficient endosomal escape after being endocytosed. Therefore, we tested a fusion protein of the ribosome‐inactivating protein dianthin and human epidermal growth factor in combination with a glycosylated triterpene (SO1861) that serves as an endosomal escape enhancer. In vitro investigations with the pancreatic carcinoma cell lines BxPC‐3 and MIA PaCa‐2 revealed no significant differences to off‐target cells in the half maximal inhibitory concentration (IC 50) for the fusion protein. In contrast, combination with SO1861 decreased the IC 50 for BxPC‐3 cells from 100 to 0.17 nm, whereas control cells remained unaffected. Monotherapy of BxPC‐3 xenografts in CD‐1 nude mice led to a 51.7% average reduction in tumor size (40.8 mm3) when compared to placebo; however, combined treatment with SO1861 resulted in a more than 13‐fold better efficacy (3.0 mm3 average tumor size) with complete regression in 80% of cases. Immunohistochemical analyses showed that tumor cells with lower target receptor expression are, in contrast to the combination therapy, able to escape from the monotherapy, which finally results in tumor growth. At the effective concentration, we did not observe liver toxicity and saw no other side effects with the exception of a reversible skin hardening at the SO1861 injection site, alongside an increase in platelet counts, plateletcrit, and platelet distribution width. In conclusion, combining a targeted toxin with SO1861 is proven to be a very promising approach for pancreatic cancer treatment.

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Epidermal Growth Factor Receptor in Pancreatic Cancer

Cited by 134 publications

References 51 publications

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpeneSO1861

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