c-erbB-2 oncogene encodes a growth factor receptor whose amino acid sequence has extensive homology with human epidermal growth factor receptor. It is frequently overexpressed in human breast, ovary, lung, and stomach cancers, where its overexpression is related significantly to the prognosis. Tl investigate the possible role of c-erbB-2 oncogene in the oncogenesis of stomach cancer, we examined the genetic alterations of c-erbB-2 oncogene in 4 stomach cancer cell lines, SNU-1, SNU-5, SNU-16 and KATO III. There were no differences in c-erbB-2 mRNA level as well as c-erbB-2 gene copy number among them. But gp185-erbB-2, c-erbB-2 gene product, was increased from 2- to 4-fold in SNU-1 and SNU-5 cells, compared with that in SNU-16 or KATO III cells. Our results suggest that post-transcriptional regulation of gp185erbB-2 expression may underlie gp185erbB-2 overexpression in cancer cells.
Amino Acid Sequence ; Humans ; Molecular Sequence Data ; Protein-Tyrosine Kinases/*biosynthesis ; Proto-Oncogene Proteins/*biosynthesis/genetics/immunology ; RNA, Messenger/analysis ; Receptor, Epidermal Growth Factor/*biosynthesis/genetics/immunology ; Receptor, erbB-2 ; Receptors, Cell Surface/*biosynthesis ; Stomach Neoplasms/genetics/*metabolism ; Tumor Cells, Cultured

Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.
Biology* ; Blood-Brain Barrier ; Brain* ; Breast Neoplasms ; Epidermal Growth Factor* ; Humans* ; Incidence ; Molecular Weight ; Neoplasm Metastasis* ; Protein-Tyrosine Kinases ; Radiation-Sensitizing Agents ; Radiosurgery ; Radiotherapy ; Receptor, Epidermal Growth Factor* ; Receptor, erbB-2 ; Trastuzumab

Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.
Drug Resistance* ; Epidermal Growth Factor* ; Hepatocyte Growth Factor ; Humans ; Lung ; Lymphoma* ; Phosphotransferases* ; Protein Kinase Inhibitors ; Protein-Tyrosine Kinases ; Receptor Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor*

Vandetanib is a once-daily oral anticancer drug that selectively inhibits key signaling pathways in cancer by targeting vascular endothelial growth factor receptors, epidermal growth factor receptors tyrosine kinase, and rearranged during transfection-dependent tumor cell proliferation and survival. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QT interval prolongation, and hypertension. Though a number of randomized, doubleblind studies, including cutaneous adverse events attributed to vandetanib, have been reported along with these general symptoms, no case of Stevens-Johnson syndrome (SJS) has been reported. This paper demonstrates a case of SJS induced by vandetanib.
Carcinoma, Non-Small-Cell Lung ; Cell Proliferation ; Diarrhea ; Hypertension ; Piperidines ; Protein-Tyrosine Kinases ; Quinazolines ; Receptor, Epidermal Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Stevens-Johnson Syndrome

PURPOSE: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor (EGFR) and shares intrinsic tyrosine kinase activity. The HER2 gene has been found to be amplified in various human cancers and to be associated with poor prognosis. The authors investigated the correlation between clinicopathologic factors and the overexpression of the p185(HER2) in Korean gastric adenocarcinoma patients, and determined whether the antiproliferative effects of anti- p185(HER2) antibody can also be observed on gastric cancer cell lines that overexpress this growth factor receptor. MATERIALS AND METHODS: We evaluated the relationship between p185(HER2) overexpression and clinicopathological features in 94 (M: F=52: 42) gastric adenocarcinoma patients (median age 59 years). Protein expression was analysed by immunohistochemical staining in paraffin embedded tissues with monoclonal antibody for p185(HER2). To explore the role of humanized anti-p185(HER2) monoclonal antibody trastuzumab (Herceptin ) in vitro, the growth curve of Korean gastric cancer cells that overexpress the p185(HER2) protein was studied and a cell cycle analysis was performed. RESULTS: p185(HER2) overexpression correlates positively with lymph node metastasis (p=0.002), distant metastasis (p=0.01), AJCC classification (p=0.01), higher relapse rate p=0.001), and a tendential association with the pT stage (p=0.054). p185(HER2) overexpression was found to be more frequent in advanced gastric cancer than early gastric cancer (54.1% vs 24.2%, p=0.008). Patients with overexpression of p185(HER2) were found to have significantly lower relapse-free (p=0.003) and overall survival (p= 0.0004) than patients without overexpression. Among several Korean gastric cancer cell lines, SNU-1, SNU-5, and SNU-620 overexpress p185(HER2). Trastuzumab inhibited the proliferation of p185(HER2) overexpressed Korean gastric cancer cell line by 21% with down-regulation of p185(HER2) protein expression. DNA fluorescence flow cytometry of propidium iodide-stained nuclei showed a reduction in the fraction of the S phase following treatment with trastuzumab. CONCLUSIONS: Taken together, our observations suggest the potential prognostic significance of p185(HER2) overexpression in Korean gastric adenocarcinoma patients and point to the need for further research on this mechanism. This suggests the possible use of p185(HER2) as a therapeutic target in gastric cancer.
Adenocarcinoma ; Cell Cycle ; Cell Line* ; Classification ; DNA ; Down-Regulation ; Flow Cytometry ; Fluorescence ; Genes, erbB-2 ; Glycoproteins ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Paraffin ; Prognosis ; Propidium ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Recurrence ; S Phase ; Stomach Neoplasms ; Trastuzumab

BACKGROUND: Statins are used to treat hypercholesterolemia; however, major cardiovascular events are decreased only 30% by statin treatment. Treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been reported to decrease serum glucose levels and improved insulin sensitivity in mice and humans, but there was no study in serum cholesterol levels. This study examined the effect of gefitinib, an EGFR tyrosine kinase inhibitor, on cholesterol metabolism in humans. METHODS: We retrospectively reviewed the medical records of 299 patients with primary lung cancer treated with gefitinib for ≥1 month and 72 patients with other treatments. Serum cholesterol, serum triglycerides, and body mass index were measured before and after treatment. The changes in serum cholesterol, serum triglycerides, and body mass index were compared between the gefitinib treatment group and the control group and were also analyzed according to the presence or absence of EGFR mutations. RESULTS: Serum cholesterol levels decreased significantly from 178.9 to 164.4 mg/dL after 1-month of gefitinib treatment. A total of 54 of the 299 patients underwent examination for the presence of the EGFR mutations. Serum cholesterol was significantly decreased in the group with the activating EGFR mutation (Δ=21.3 mg/dL) compared to that of those without the EGFR mutation (Δ=-3.1 mg/dL) after treatment with gefitinib. In contrast, there was no significantly difference between the two groups in control patients. CONCLUSION: Treatment with gefitinib decreased serum cholesterol in lung cancer patients, particularly in those with activating mutations in EGFR. These data suggest that EGFR tyrosine kinase inhibitors provide a novel and attractive strategy for the treatment of hypercholesterolemia.
Animals ; Blood Glucose ; Body Mass Index ; Cholesterol ; Epidermal Growth Factor ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypercholesterolemia ; Insulin Resistance ; Lung Neoplasms ; Lung ; Medical Records ; Metabolism ; Mice ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Retrospective Studies ; Triglycerides

Vandetanib (ZD6474, Zactima(TM)) is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis, including vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QC interval prolongation, and hypertension. In a few randomized, double-blinded studies, cutaneous adverse events including these general symptoms have been reported, but there are only a few reports on the photosensitivity reaction to vandetanib domestically as conducted by dermatologists. In this report, we describe two cases of photosensitivity reactions induced by vandetanib. After improvement with steroid and antihistamine, the photosensitivity reaction was redeveloped by sequential treatment with docetaxel.
Diarrhea ; Hypertension ; Piperidines ; Protein-Tyrosine Kinases ; Quinazolines ; Receptor, Epidermal Growth Factor ; Taxoids ; Transfection ; Vascular Endothelial Growth Factor Receptor-2

ZD1839 (Iressa(R)) is a new anticancer agent, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathway implicated in the proliferation and survival of cancer cells and other host-dependent process promoting cancer growth. But this agent can induce cutaneous side effects including acneiform eruption, dry skin, and hair abnormality, which is related with the interruption of normal epidermal and hair follicular kinetics. We report a case of hair change and acneiform eruption induced by ZD1839 (Iressa(R)).
Acneiform Eruptions* ; Hair* ; Kinetics ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Signal Transduction ; Skin

epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors, new therapeutic strategies are needed to improve clinical outcomes. Immunotherapy through the use of immune checkpoint inhibitors has provided one of the most important breakthroughs in the management of solid tumors, including lung cancers, and has shown promising results in numerous clinical trials. This review will present the current status of immunotherapy for lung cancer and future perspectives on these treatments.]]>
Immunotherapy ; Lung Neoplasms ; Lung ; Lymphoma ; Phosphotransferases ; Prognosis ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

OBJECTIVETo evaluate the expression of the type I growth factor receptor family [epidermal growth factor receptor (EGFR), ErbB2 and ErbB3] by the epithelial cells in pterygium.

METHODSImmunoflourescent staining and Western blotting were performed to detect the expression pattern and quantity of EGFR, ErbB2 and ErbB3 proteins in the epithelia of 15 patients with primary pterygium and 12 subjects with normal conjunctiva.

RESULTSIn immunofluorescent staining, the EGFR protein was present in the basal cells while the ErbB2 and ErbB3 were expressed by the superficial cells in normal conjunctival epithelium. Of the pterygium cases 15, 11 were stained by EGFR, ErbB2 and ErbB3 in the full thickness of the epithelium and showed stronger staining compared with the control group. Four of them showed a similar staining pattern to the normal conjunctiva group. The density of protein bands detected by Western blotting for all three growth factor receptors was consistent with the immunofluorescent staining. Compared with normal conjunctiva, stronger protein bands of these three receptors were found in all of the pterygium specimens, in which EGFR, ErbB2 and ErbB3 were expressed in the full thickness, as shown by immunofluorescent staining.

CONCLUSIONSThe increased expression of EGFR, ErbB2 and ErbB3 proteins was present in pterygium, which indicated that pterygium is a disorder with abnormal proliferation. The abnormal expression of EGFR, ErbB2 and ErbB3 by the epithelium and the communication with cytokines in the stroma in pterygium may be a key pathogenic factor in this disorder.

Adult ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Pterygium ; metabolism ; Receptor, Epidermal Growth Factor ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, ErbB-3 ; metabolism