Investigational therapies targeting the ErbB (EGFR, HER2, HER3, HER4) family in GI cancers

Desai, Monica Dandona; Saroya, Bikramajit Singh; Lockhart, A. Craig

doi:10.1517/13543784.2013.761972

Cited by 25 publications

(26 citation statements)

References 105 publications

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“…EGF binding to cell membrane EGFR triggers EGFR conformational change to allow homodimerization with another EGFR or heterodimerization with another ErbB family and then induces receptor activation followed by subsequent receptor internalization to the early endosome. In the early endosome, EGFR is either recycled back to the cell surface or sorted to the late endosome/lysosome for degradation in termination of signal transduction [26–28]. Several studies have shown that EGFR is capable of recruiting signaling molecules and transmit signals from endosome [29–32], however, a recent study reports that EGFR signaling takes place primarily at the plasma membrane and the function of EGFR internalization is to terminate signals induced by EGF binding to plasma membrane EGFR [33].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling

Huang

Chou

et al. 2015

Oncotarget

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O-glycosylation is a common protein modification. Aberrant O-glycosylation is associated with many cancers. GALNT1 is a GalNAc-transferase that initiates protein O-glycosylation. We found that GALNT1 is frequently up-regulated in hepatocellular carcinoma (HCC) and is associated with poor patient survival. Overexpression of GALNT1 increased and knockdown decreased HCC cell migration and invasion. Knockdown of GALNT1 inhibited EGF-induced migration and invasion. Knockdown of GALNT1 decreased EGFR activation and increased EGFR degradation, by decreasing EGFR O-glycosylation. This study demonstrates that down-regulation of GALNT1 is sufficient to suppress malignant phenotype of HCC cells by decreasing EGFR signaling. Thus, GALNT1 is a potential target in HCC.

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Section: Discussionmentioning

confidence: 99%

Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling

Huang

Chou

et al. 2015

Oncotarget

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“…The MAPK pathway, frequently upregulated in HCC [37], includes a cascade of phosphorylation of four major cellular kinases, Ras, Raf, mitogen-activated protein extracellular kinase (MEK), and extracellular signal-regulated kinase (ERK) [38]. …”

Section: Hepatocarcinogenesismentioning

confidence: 99%

Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

Bertino

Demma

Ardiri

et al. 2014

BioMed Research International

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Background Hepatocellular carcinoma is one of the most common and lethal malignant tumors worldwide. Over the past 15 years, the incidence of HCC has more than doubled. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with HCC. A better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Materials and Methods A search of the literature was made using cancer literature, the PubMed, Scopus, and Web of Science (WOS) database for the following keywords: “hepatocellular carcinoma,” “molecular hepatocarcinogenesis,” “targeted therapy,” and “immunotherapy.” Discussion and Conclusion. Treatment decisions are complex and dependent upon tumor staging, presence of portal hypertension, and the underlying degree of liver dysfunction. The knowledge of molecular hepatocarcinogenesis broadened the horizon for patients with advanced HCC. During the last years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. In the future, new therapeutic options will be represented by a blend of immunotherapy-like vaccines and T-cell modulators, supplemented by molecularly targeted inhibitors of tumor signaling pathways.

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“…ErbB2 receptor is a 175-kDa glycoprotein that lacks a known ligand and therefore relies on heterodimerization with other EGFR family members for signaling. Dimerization of ErbBs results in activation of multiple downstream signalling pathways such as the mitogenic Ras/Raf/extracellular-signal-regulated kinase 1/2 (ERK1/2), the p38 mitogen activated protein (MAP) kinase or the PI3-kinase/Akt survival pathways [7]–[10]. Alternatively, transactivation of ErbBs can occur via G-protein coupled receptors (GPCRs), such as angiotensin II (Ang II), thrombin, aldosterone and endothelin [11]–[15].…”

Section: Introductionmentioning

confidence: 99%

Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction

et al. 2013

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Diabetes mellitus leads to vascular complications but the underlying signalling mechanisms are not fully understood. Here, we examined the role of ErbB2 (HER2/Neu), a transmembrane receptor tyrosine kinase of the ErbB/EGFR (epidermal growth factor receptor) family, in mediating diabetes-induced vascular dysfunction in an experimental model of type 1 diabetes. Chronic treatment of streptozotocin-induced diabetic rats (1 mg/kg/alt diem) or acute, ex-vivo (10−6, 10−5 M) administration of AG825, a specific inhibitor of ErbB2, significantly corrected the diabetes-induced hyper-reactivity of the perfused mesenteric vascular bed (MVB) to the vasoconstrictor, norephinephrine (NE) and the attenuated responsiveness to the vasodilator, carbachol. Diabetes led to enhanced phosphorylation of ErbB2 at multiple tyrosine (Y) residues (Y1221/1222, Y1248 and Y877) in the MVB that could be attenuated by chronic AG825 treatment. Diabetes- or high glucose-mediated upregulation of ErbB2 phosphorylation was coupled with activation of Rho kinases (ROCKs) and ERK1/2 in MVB and in cultured vascular smooth muscle cells (VSMC) that were attenuated upon treatment with either chronic or acute AG825 or with anti-ErbB2 siRNA. ErbB2 likley heterodimerizes with EGFR, as evidenced by increased co-association in diabetic MVB, and further supported by our finding that ERK1/2 and ROCKs are common downstream effectors since their activation could also be blocked by AG1478. Our results show for the first time that ErbB2 is an upstream effector of ROCKs and ERK1/2 in mediating diabetes-induced vascular dysfunction. Thus, potential strategies aimed at modifying actions of signal transduction pathways involving ErbB2 pathway may prove to be beneficial in treatment of diabetes-induced vascular complications.

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Investigational therapies targeting the ErbB (EGFR, HER2, HER3, HER4) family in GI cancers

Cited by 25 publications

References 105 publications

Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling

Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling

Hepatocellular Carcinoma: Novel Molecular Targets in Carcinogenesis for Future Therapies

Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction

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