Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma

Liu, Yuqing; Poon, Ronnie T. P.; Shao, Weijuan; Sun, Xiaoli; Chen, Hui; Kok, Tsz Wai; Fan, Sheung Tat

doi:10.1016/j.canlet.2006.05.018

Cited by 27 publications

(14 citation statements)

References 18 publications

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“…In this study, AG1478 downregulated phosphorylation of ERK and Akt in A431 cells with overexpression of EGFR. This finding suggests that EGFR inhibitor inhibits the activation of the antiapoptotic molecules downstream of EGFR in vulvar cancer cells, which is in agreement with other studies about the efficacy of the EGFR inhibitor in EGFR‐expressing cancer cells 20–22 . However, phosphorylation of Akt in A431 cells was not completely suppressed, despite a complete inhibition of EGFR activation.…”

Section: Discussionsupporting

confidence: 91%

Effect of Epidermal Growth Factor Receptor Inhibitor Alone and in Combination with Cisplatin on Growth of Vulvar Cancer Cells

Kim¹,

Song²,

Kim³

et al. 2009

Annals of the New York Academy of Sciences

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A recent study reported on the efficacy of the EGFR inhibitor on locally advanced vulvar cancer. The aim of this study was to evaluate the effect of an EGFR tyrosine kinase inhibitor (AG1478) alone and in combination with cisplatin on vulvar cancer cells (A431 and SW962). We detected overexpression of EGFR in A431 cells and low expression in SW962 cells. We found that the growth inhibitory effect of AG1478 was dependent upon the expression level of EGFR. The combined treatment of AG1478 with cisplatin failed to exert any synergistic or additive effect in either cell line. In the EGFR signaling pathway, AG1478 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in parallel with decreased activity of EGFR in A431 cells, while no changes in ERK and Akt were observed in SW962 cells. The combination of AG1478 with cisplatin completely inhibited the phosphorylation of ERK and Akt in A431 cells but not in SW962 cells. Cisplatin alone and its combination with AG1478 increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) in both cell lines. In summary, AG1478 inhibited the growth activity of vulvar cancer cells, depending upon the expression level of EGFR, by inhibiting the activities of EGFR, Akt, and ERK. Given the absence of synergistic effects from the combination of AG1478 with cisplatin, combination therapy should be considered cautiously.

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Section: Discussionsupporting

confidence: 91%

Effect of Epidermal Growth Factor Receptor Inhibitor Alone and in Combination with Cisplatin on Growth of Vulvar Cancer Cells

Kim¹,

Song²,

Kim³

et al. 2009

Annals of the New York Academy of Sciences

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“…Gefitinib has also been shown to inhibit metastastic property of HCC in a mouse model [105]. A study from our group demonstrated the antitumor effect of two other EGFR tyrosine kinase inhibitors in HCC [106]. …”

Section: Molecular Targets For Therapy In Hccmentioning

confidence: 99%

From Molecular Biology to Targeted Therapies for Hepatocellular Carcinoma: The Future Is Now

Pang¹,

2007

Self Cite

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Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.

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“…The EGFR inhibitors PD153035 and its analogue 4-[[3-chloro-4-fluorophenyl]amino]-6,7-dimethoxyquinazoline hydrochloride (ANAPD) inhibit the growth and induce apoptosis of human HCC cell lines in a dosedependent manner (Fig. 7) [208]. These specific inhibitors block EGF-stimulated EGFR autophosphorylation and targeted EGFR signaling including MAPK and AKT pathways.…”

Section: Cell Signaling Inhibitorsmentioning

confidence: 98%

Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

Calvisi¹,

Pascale²,

Feo

2007

RRCT

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Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.

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Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma

Cited by 27 publications

References 18 publications

Effect of Epidermal Growth Factor Receptor Inhibitor Alone and in Combination with Cisplatin on Growth of Vulvar Cancer Cells

Effect of Epidermal Growth Factor Receptor Inhibitor Alone and in Combination with Cisplatin on Growth of Vulvar Cancer Cells

From Molecular Biology to Targeted Therapies for Hepatocellular Carcinoma: The Future Is Now

Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

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