Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy

Richardson, Catherine M.; Sharma, Ricky A.; Cox, G.; O’Byrne, Kenneth J.

doi:10.1016/s0169-5002(02)00382-3

Cited by 47 publications

(24 citation statements)

References 91 publications

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“…Therapeutic targeting of the EGFR with EGFR tyrosine kinase inhibitors, such as erlotinib, has achieved beneficial results in unselected NSCLC patients (11). This has included dramatic responses, most often observed in patients with EGFR mutant tumors, as well as clinically significant stabilization of disease, often observed in patients without EGFR mutant tumors.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer

Yang

Amann²,

Kikuchi

et al. 2007

Cancer Research

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Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E 2 (PGE 2 ) levels contribute to the pathogenesis of non-small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE 2 concentrations also depend upon the levels of the PGE 2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE 2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI. [Cancer Res 2007;67(12):5587-93]

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Section: Resultsmentioning

confidence: 99%

Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer

Yang

Amann²,

Kikuchi

et al. 2007

Cancer Research

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“…Both EGFR and COX-2 are overexpressed in NSCLC and have been implicated in tumorigenesis and EGFR-TKI combined with COX-2 inhibitors treatment are rousing interest in recent years [44,45]. In colon cancer, breast cancer, and head and neck cancer, a few in vitro studies have shown the preliminary synergistic growth inhibition effect of EGFR-TKI combined with COX-2 inhibitor whereas no report in NSCLC [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study

Chen

Huang

et al. 2008

Med Oncol

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Constitutive expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) occurs frequently in non-small cell lung cancer (NSCLC). Anticancer research targeting EGFR has got an extensive attention especially in NSCLC and COX-2 inhibitor also shown a certain anticancer activity in recent years. Simultaneously targeting COX-2 and EGFR may be a promising therapeutic way. We carried out the in vitro study using selective COX-2 inhibitor celecoxib combined with EGFR-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 on NSCLC cell lines to investigate the anti proliferation effect and the cell molecular mechanism. MTT growth assay showed the synergistic therapeutic effect of certain concentration of celecoxib combined with ZD1839 and synergistic apoptosis effect was detected by Hoechest33258 fluorescence staining and flow cytometric analysis. In western blot analysis, ZD1839 single agent inhibited the activation of EGFR and downstream cell signal transduction AKT and extrocellular signal-regulated kinase (ERK) pathways, the transcription activity of nuclear factor-kappa B (NF-kappaB), and the expression of COX-2. Celecoxib single agent could also inhibit AKT and ERK pathway in NSCLC, even the EGFR expression under high concentration treatment. Celecoxib combined with ZD1839 led to stronger inhibition of related cell signal transduction pathways in NSCLC.

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“…11 These observations have been supported by a number of other studies and COX-2 inhibition continues to be explored as a chemopreventative and therapeutic target in NSCLC and other diseases. [14][15][16][17] Role of TNF-α, IL-1β and hypoxia Chronic inflammation has been linked with the development of a number of solid cancers, [18][19][20][21][22] with TNF-α 23,24 as one of the major mediators of cancer-related inflammation. As a tumor-promoting factor, it is linked to transformation, proliferation, angiogenesis and metastasis in many cancers.…”

Section: Bioactive Lipidsmentioning

confidence: 99%

Stimulating immune responses to fight cancer: Basic biology and mechanisms

O’Byrne

2015

Asia-Pac J Clncl Oncology

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Chronic inflammation is now recognized as a major cause of malignant disease. In concert with various mechanisms (including DNA instability), hypoxia and activation of inflammatory bioactive lipid pathways and pro-inflammatory cytokines open the doorway to malignant transformation and proliferation, angiogenesis, and metastasis in many cancers. A balance between stimulatory and inhibitory signals regulates the immune response to cancer. These include inhibitory checkpoints that modulate the extent and duration of the immune response and may be activated by tumor cells. This contributes to immune resistance, especially against tumor antigen-specific T-cells. Targeting these checkpoints is an evolving approach to cancer immunotherapy, designed to foster an immune response. The current focus of these trials is on the programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1, PD-L2) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Researchers have developed anti-PD-1 and anti-PDL-1 antibodies that interfere with the ligands and receptor and allow the tumor cell to be recognized and attacked by tumor-infiltrating T-cells. These are currently being studied in lung cancer. Likewise, CTLA-4 inhibitors, which have had success treating advanced melanoma, are being studied in lung cancer with encouraging results.

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Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy

Cited by 47 publications

References 91 publications

Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer

Inhibition of Epidermal Growth Factor Receptor Signaling Elevates 15-Hydroxyprostaglandin Dehydrogenase in Non–Small-Cell Lung Cancer

Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study

Stimulating immune responses to fight cancer: Basic biology and mechanisms

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