Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor Tyrosine Kinases class I (RTK class I, EGF receptor family) constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand. In contrast, activation of HER2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligand-independent manner. EGFR and HER2 have now been validated as a clinically relevant target, and several different types of agents inhibiting these receptors are currently in development. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors. Several of the other erbB inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. This review reports various inhibitors, natural, small molecules and monoclonal antibodies, along with their reported activities for various members of erbB family. It will highlight the potential for the development of novel anti-cancer molecules.
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PMID:Receptor tyrosine kinase inhibitors as potent weapons in war against cancers. 1927 41

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.
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PMID:Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. 1934 11

Epidermal growth factor receptor inhibitors (EGFRIs) are new anticancer agents that act by inhibiting EGFR signaling transduction pathways, thus decreasing tumor growth. In more than 30 countries, EGFRIs are currently used in the treatment of a number of solid tumors, and other indications are being sought. In the United States, select EGFRIs have been approved in certain patients with non-small cell lung cancer, metastatic colorectal carcinoma, and advanced squamous cell carcinoma of the head and neck. Various cutaneous side effects of EGFRIs have been reported, including acneiform eruptions, chronic paronychia, xerosis, a seborrheic dermatitis-like eruption, changes in hair texture, and nonscarring alopecia. We present a 60-year-old woman with non-small cell lung cancer who developed a persistent generalized itchy eruption and progressive nonscarring alopecia shortly after initiation of erlotinib (Tarceva). Scalp biopsy showed near-equal number of anagen and catagen/telogen hair follicles, and a superficial and deep perivascular lymphoplasmocytic infiltration. These changes are typical of the nonscarring alopecia induced by EGFRIs. Because it is likely that EGFRIs will be increasingly used, dermatopathologists are likely to see more reactions from these agents. Familiarity with their side effects is essential to accurate diagnosis and effective patient management.
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PMID:A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib. 1951 75

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
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PMID:Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. 1956 54

EGFR receptor is expressed on most of the non small cell lung carcinoma (NSCLC) cells. Its relative importance in oncogenesis and tumour progression seems to greatly vary among NSCLC. Two molecules targeting differently EGFR are currently used for the treatment of metastatic NSCLC. cetuximab, a monoclonal antibody directed against the extracellular domain of the receptor, leads to a moderate survival benefit when associated with standard first-line chemotherapy. Erlotinib, a small EGFR tyrosine-kinase inhibitor molecule is used in 2nd or 3rd treatment line. Predictive factors for efficiency of these new treatments are subjects of intense research, in order to allow a better selection of the patients who could benefit from such a strategy.
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PMID:[The role of EGFR in non-small cell lung carcinoma]. 1958 Feb 6

1. Erlotinib, a small-molecule epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, has been approved for the management of advanced non-small cell lung cancer. The aim of the present study was to investigate whether erlotinib exerts potent antitumour activities through the reactive oxygen species (ROS)-c-Jun N-terminal kinase (JNK) pathway in the human non-small cell lung cancer cell line A549. 2. The 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and Hoechst 33342 staining showed that erlotinib produced a decline in cell viability of A549 cells and induced cell apoptosis, coupled with quick accumulation of ROS. In addition, erlotinib increased the respiratory control ratio, NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion (O2(-)) generation, suggesting that erlotinib induced ROS production in A549 cells from both mitochondrial and NADPH oxidase sources. 3. Fluorescence microscopy with the JC-1 probe and western blot analysis indicated that erlotinib induced loss of mitochondrial membrane potential, the release of cytochrome c and apoptosis-inducing factor (AIF) and activation of JNK. 4. The results of the present study suggest that erlotinib has potent antitumour activity in A549 cells by activating ROS-dependent, JNK-driven cell apoptosis. These findings provide a novel insight into the mechanism of action of erlotinib in the treatment of human non-small cell lung cancer in addition to its effects in inhibiting EGFR-TK.
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PMID:Erlotinib activates mitochondrial death pathways related to the production of reactive oxygen species in the human non-small cell lung cancer cell line A549. 1967 30

Pancreatic cancer has proven to be chemo-resistant, with gemcitabine being the only cytotoxic agent approved for advanced pancreatic cancer since 1996. Tyrosine kinase inhibitors represent a newer generation of chemotherapeutic agents targeting specific tumor pathways associated with carcinogenesis including cell cycle control, signal transduction, apoptosis and angiogenesis. These agents present a more selective way of treating pancreatic cancer. Erlotinib is the prototype of the tyrosine kinase inhibitors with proven efficacy in advanced pancreatic cancer and has been recently approved in that setting. Multiple other tyrosine kinase inhibitors targeting the VEGFR, PDGFR, and Src kinases are in various phases of clinical trials testing. The preliminary results of these trials have been disappointing. Current challenges in pancreatic cancer clinical trials testing include improving patient selection, identifying effective combinations, improving the predictive value of current preclinical models and better study designs. This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development.
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PMID:Small molecule tyrosine kinase inhibitors in pancreatic cancer. 1970 51

Lung cancer is the most common tumor-related cause of death in western industrialized countries, despite continuous improvement in both diagnostic and therapeutic approaches. Since epidermal growth factor receptor (EGFR) is overexpressed in 80% of cases of non-small cell lung carcinoma, mediating important carcinogenic properties such as cell-cycle progression, apoptosis, angiogenesis and metastasis, it is considered a relevant target in novel specific therapies. This has lead to the development of the low-molecular EGFR tyrosine kinase inhibitors (EGFR-TKI) Gefitinib and Erlotinib. Predicting which patients will respond to an EGFR-targeted therapy is of particular clinical interest. Recent studies show a significantly better response and prolonged progression-free survival in patients with EGFR-mutated tumors, even when used as first-line therapy. Moreover, genetic mutations which correlate to primary EGFR-TKI resistance (e.g. KRAS) or produce secondary resistance to known TKI (e.g. EGFR mutation T790 M or MET amplification) have meanwhile been explained. Predictive diagnosis of these mutations using histological material is becoming increasingly important for patient stratification and will soon be indispensable not only for lung cancer.
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PMID:[Molecular diagnostics in lung carcinoma for therapy stratification]. 1999 36

Erlotinib is increasingly being used for the treatment of non-small cell lung cancer. The recommended dose is 150 mg/day and no efficacy data is available for lower doses. We describe a case of dramatic tumor response to 50 mg erlotinib in a patient with EGFR mutation positive NSCLC who developed a severe rash on full dose erlotinib. Rash is known to correlate with response and survival in patients treated with erlotinib. Our case suggests that in the presence of rash, dose reductions to "subtherapeutic" levels remain effective and may prevent unnecessary early treatment termination.
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PMID:Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-positive recurrent non-small cell lung cancer after severe cutaneous toxicity. 2000 14

Erlotinib has been FDA approved to be used in combination with gemcitabine as the first line treatment in advanced pancreatic cancer patients. Skin rash has been documented as one of the commonest adverse reactions in patients receiving erlotinib and other EGFR inhibitors. Draw back to this reaction leads to: 1) drug discontinuation or dose reduction; 2) impairs quality of life; and 3) Puts patients at risk of superinfection. Monitoring patients closely and initiating immediate skin care is recommended. However, patients forget how the rash started and when. No standard treatments exist secondary to the diversity of symptoms, variability and intermittent occurrence in relation to the cancer therapy. In addition, there is slow improvement with medical treatment. Also, patients need to make extra visits to doctor's office for skin management when in needed in addition to chemotherapy appointments. Late presentation for medical attention leading to complications, such as sepsis. We here experience a novel way of assessing and managing the skin rash using the electronic media. We suggest that electronic communication is of crucial importance to detect early, diagnose and treat anti-EGFR related skin rash in order to continue the benefit of anti-EGFR.
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PMID:Management of skin toxicities of anti-EGFR agents in patients with pancreatic cancer and other GI tumors by using electronic communication: effective and convenient. 2020 31


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